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Root hairs (RHs) are an innovation of vascular plants whose development is coordinated by endogenous and environmental cues, such as ethylene and light conditions. However, the potential crosstalk between ethylene and light conditions in RH development is unclear. We report that Arabidopsis constitutive photomorphogenic 1 (COP1) integrates ethylene and light signaling to mediate RH development. Darkness suppresses RH development largely through COP1. COP1 inhibits both cell fate determination of trichoblast and tip growth of RHs based on pharmacological, genetic, and physiological analyses. Indeed, COP1 interacts with and catalyzes the ubiquitination of ACS2 and ACS6. COP1- or darkness-promoted proteasome-dependent degradation of ACS2/6 leads to a low ethylene level in underground tissues. The negative role of COP1 in RH development by downregulating ethylene signaling may be coordinated with the positive role of COP1 in hypocotyl elongation by upregulating ethylene signaling, providing an evolutionary advantage for seedling fitness. [Display omitted] • Root hairs respond to light or ethylene by increasing both density and length • Arabidopsis COP1, the light responsive factor, inhibits root hair development • COP1 catalyzes the ubiquitination of type I ACSs to reduce ethylene responses • Dark-induced 26S-proteasome-mediated degradation of type I ACSs largely depends on COP1 Yin et al. report that Arabidopsis constitutive photomorphogenic 1 (COP1), a light response factor, controls root hair development by catalyzing the ubiquitination of type I ACSs and degradation to inhibit ethylene biosynthesis. The negative role of COP1 in root hairs may coordinate with its positive role in hypocotyl elongation to promote seedling fitness. [ABSTRACT FROM AUTHOR]

In multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells or extrinsic interactions that produce specific patterns of descendant cell types on lineage trees. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer these dynamics and understand how they establish overall cell type proportions. Here, we introduce Lineage Motif Analysis (LMA), a method that recursively identifies statistically overrepresented patterns of cell fates on lineage trees as potential signatures of committed progenitor states or extrinsic interactions. Applying LMA to published datasets reveals spatial and temporal organization of cell fate commitment in zebrafish and rat retina and early mouse embryonic development. Comparative analysis of vertebrate species suggests that lineage motifs facilitate adaptive evolutionary variation of retinal cell type proportions. LMA thus provides insight into complex developmental processes by decomposing them into simpler underlying modules. [Display omitted] • Lineage motifs are overrepresented patterns of cell fates on lineage trees • Lineage motifs could reflect committed progenitors or extrinsic interactions • Lineage motifs are identified in existing retina and early embryo lineage datasets • Lineage motifs could facilitate adaptive variation in cell type proportions Biological tissues require fine-tuned cell type proportions for optimal function, but how this process is regulated remains poorly understood. Tran et al. suggest that lineage motifs reflect modular developmental programs that could constrain variation in cell type proportions. [ABSTRACT FROM AUTHOR]

Summary Wnt/β-Catenin signaling plays key roles in tissue homeostasis and cell fate decisions in embryonic and post-embryonic development across the animal kingdom. As a result, pathway mutations are associated with developmental disorders and many human cancers. The multiprotein destruction complex keeps signaling off in the absence of Wnt ligands and needs to be downregulated for pathway activation. We discuss new insights into destruction complex activity and regulation, highlighting parallels to the control of other cell biological processes by biomolecular condensates that form by phase separation to suggest that the destruction complex acts as a biomolecular condensate in Wnt pathway regulation. Wnt/β-Catenin signaling controls tissue homeostasis and cell fate decisions. The multiprotein destruction complex suppresses signaling in absence of Wnt ligand and is downregulated for pathway activation. Schaefer and Peifer discuss new insights into destruction complex activity and regulation, highlighting evidence that it acts as a biomolecular condensate in pathway control. [ABSTRACT FROM AUTHOR]

Hair-like structures are shared by most living organisms. The hairs on plant surfaces, commonly referred to as trichomes, form diverse types to sense and protect against various stresses. However, it is unclear how trichomes differentiate into highly variable forms. Here, we show that a homeodomain leucine zipper (HD-ZIP) transcription factor named Woolly controls the fates of distinct trichomes in tomato via a dosage-dependent mechanism. The autocatalytic reinforcement of Woolly is counteracted by an autoregulatory negative feedback loop, creating a circuit with a high or low Woolly level. This biases the transcriptional activation of separate antagonistic cascades that lead to different trichome types. Our results identify the developmental switch of trichome formation and provide mechanistic insights into the progressive fate specification in plants, as well as a path to enhancing plant stress resistance and the production of beneficial chemicals. [Display omitted] • Woolly governs trichome differentiation in a concentration-dependent mode • Woolly levels result from opposing actions between self-activation and negative feedback • SlWox3b/MX1 and LFS promote the fate of digitate and peltate trichomes, respectively • High Woolly levels preferentially activate SlWox3b/MX1, which can repress LFS expression In plants, hair-like structures known as trichomes， form different types with diverse shapes and functions for protection but the mechanism of trichome differentiation remains unclear. Wu et al. demonstrate that a HD-ZIP transcription factor can establish the cell fate landscape of tomato trichomes in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Summary Gastrulation of the mouse embryo entails progressive restriction of lineage potency and the organization of the lineage progenitors into a body plan. Here we performed a high-resolution RNA sequencing analysis on single mid-gastrulation mouse embryos to collate a spatial transcriptome that correlated with the regionalization of cell fates in the embryo. 3D rendition of the quantitative data enabled the visualization of the spatial pattern of all expressing genes in the epiblast in a digital whole-mount in situ format. The dataset also identified genes that (1) are co-expressed in a specific cell population, (2) display similar global pattern of expression, (3) have lineage markers, (4) mark domains of transcriptional and signaling activity associated with cell fates, and (5) can be used as zip codes for mapping the position of single cells isolated from the mid-gastrula stage embryo and the embryo-derived stem cells to the equivalent epiblast cells for delineating their prospective cell fates. [ABSTRACT FROM AUTHOR]

Conrad Waddington’s eponymous 1957 diagram provided a metaphorical framework for considering how sequential developmental fate decisions allow an egg to develop into an embryo. In recent years, the Waddington diagram has been repurposed to illustrate how cellular identity changes in the context of reprogramming. In this Perspective, we revisit the Waddington diagram in light of the emerging recognition that plasticity is part and parcel of adult regeneration. Specifically, we speculate that the “epigenetic landscapes” that define identity in adult tissues are dynamic, facilitating cellular de-differentiation and trans-differentiation in the setting of injury. [ABSTRACT FROM AUTHOR]

It is becoming clear that a radical change of cell identity of differentiated cells in vivo, triggered by injury or other adversity, provides an essential route to recovery for many different mammalian tissues. This process, which we term adaptive cellular reprogramming, promotes regeneration in one of two ways: by providing a transient class of repair cells or by directly replacing cells lost during tissue damage. Controlling adaptive changes in cell fate in vivo in order to promote the body’s own cell therapy, particularly by pharmacology rather than genetics, is likely to become an increasingly active area of future work. [ABSTRACT FROM AUTHOR]

Summary Epithelial cells undergo dynamic polarity changes as organs pattern, but the relationship between epithelial polarity and cell fate is poorly understood. Using the developing lung as a model, we found that distinct alterations in apical-basal polarity dictate airway epithelial differentiation. We demonstrate that Crb3, a Crumbs isoform that determines epithelial apical domain identity, is required for airway differentiation by controlling the localization of the transcriptional regulator Yap. We show that Crb3 promotes the interaction between Yap and the Hippo pathway kinases Lats1/2 at apical cell junctions to induce Yap phosphorylation and cytoplasmic retention, which drive cell differentiation. Loss of Crb3 in developing mouse airways or isolated adult airway progenitors results in unrestricted nuclear Yap activity and consequent cell differentiation defects. Our findings demonstrate that polarity-dependent cues control airway cell differentiation, offering important molecular insights into organ patterning. [ABSTRACT FROM AUTHOR]

Summary Regenerating tissue must replace lost structures with cells of the proper identity and function. How regenerating tissue establishes or maintains correct cell fates during regrowth is an open question. We have identified a gene, taranis , that is essential for maintaining proper cell fate in damaged and regenerating Drosophila wing imaginal discs but that is dispensable for these fates in normal wing development. In regenerating tissue with reduced levels of Taranis, expression of the posterior selector gene engrailed is silenced through an autoregulatory silencing mechanism that requires the PRC1 component polyhomeotic , resulting in a transformation of posterior tissue into anterior tissue late in regeneration. An essential component of the wound response, JNK signaling, induces this misregulation of engrailed expression. Taranis can suppress these JNK-induced cell fate changes without interfering with JNK signaling activity. Thus, taranis protects regenerating tissue from deleterious side effects of wound healing and regeneration. [ABSTRACT FROM AUTHOR]

Summary Developmental transitions can be described in terms of morphology and the roles of individual genes, but also in terms of global transcriptional and epigenetic changes. Temporal dissections of transcriptome changes, however, are rare for intact, developing tissues. We used RNA sequencing and microarray platforms to quantify gene expression from labeled cells isolated by fluorescence-activated cell sorting to generate cell-type-specific transcriptomes during development of an adult stem-cell lineage in the Arabidopsis leaf. We show that regulatory modules in this early lineage link cell types that had previously been considered to be under separate control and provide evidence for recruitment of individual members of gene families for different developmental decisions. Because stomata are physiologically important and because stomatal lineage cells exhibit exemplary division, cell fate, and cell signaling behaviors, this dataset serves as a valuable resource for further investigations of fundamental developmental processes. [ABSTRACT FROM AUTHOR]

Yamanaka factors are essential for establishing pluripotency in embryonic stem cells, but their function in multipotent stem cell populations is poorly understood. Here, we show that OCT4 and SOX2 cooperate with tissue-specific transcription factors to promote neural crest formation. By assessing avian and human neural crest cells at distinct developmental stages, we characterized the epigenomic changes that occur during their specification, migration, and early differentiation. This analysis determined that the OCT4-SOX2 dimer is required to establish a neural crest epigenomic signature that is lost upon cell fate commitment. The OCT4-SOX2 genomic targets in the neural crest differ from those of embryonic stem cells, indicating the dimer displays context-specific functions. Binding of OCT4-SOX2 to neural crest enhancers requires pioneer factor TFAP2A, which physically interacts with the dimer to modify its genomic targets. Our results demonstrate how Yamanaka factors are repurposed in multipotent cells to control chromatin organization and define their developmental potential. [Display omitted] • The OCT4-SOX2 dimer regulates the epigenomic landscape of neural crest (NC) cells • Dimer targets in the NC differ from those of embryonic stem cells • Pioneer factor TFAP2A interacts with OCT4-SOX2 to modify its genomic occupancy Utilizing genomic analysis to survey neural crest development, Hovland and Bhattacharya et al. identify Yamanaka factors OCT4 and SOX2 as key regulators of multipotency. The authors show how components of the pluripotency network cooperate with tissue-specific pioneer transcription factors to generate the neural crest stem cell state. [ABSTRACT FROM AUTHOR]

Summary The proteins of the Hedgehog (Hh) family are secreted proteins exerting short- and long-range control over various cell fates in developmental patterning. The Hh gradient in Drosophila wing imaginal discs consists of apical and basolateral secreted pools, but the mechanisms governing the overall establishment of the gradient remain unclear. We investigated the relative contributions of endocytosis and recycling to control the Hh gradient. We show that, upon its initial apical secretion, Hh is re-internalized. We examined the effect of the resistance-nodulation-division transporter Dispatched (Disp) on long-range Hh signaling and unexpectedly found that Disp is specifically required for apical endocytosis of Hh. Re-internalized Hh is then regulated in a Rab5- and Rab4-dependent manner to ensure its long-range activity. We propose that Hh-producing cells integrate endocytosis and recycling as two instrumental mechanisms contributing to regulate the long-range activity of Hh. [ABSTRACT FROM AUTHOR]

Summary Transcription factor complexes have varied effects on cell fate and behavior, but how this diversification of function occurs is largely unknown. The Nodal signaling pathway has many biological functions that all converge on the transcription factors Smad2/3. Smad2/3 has many cofactors, and alternative usage of these may provide a mechanism for modulating Smad2/3 function. Here, we investigate how perturbation of the cofactor E2a affects global patterns of Smad2/3 binding and gene expression during gastrulation. We find that E2a regulates early development in two ways. E2a changes the position of Smad2/3 binding at the Nodal inhibitor lefty , resulting in direct repression of lefty that is critical for mesendoderm specification. Separately, E2a is necessary to drive transcription of Smad2/3 target genes, including critical regulators of dorsal cell fate and morphogenesis. Overall, we find that E2a functions as both a transcriptional repressor and activator to precisely regulate Nodal signaling. [ABSTRACT FROM AUTHOR]

Summary: Cells of the inner cell mass (ICM) of the mouse blastocyst differentiate into the pluripotent epiblast or the primitive endoderm (PrE), marked by the transcription factors NANOG and GATA6, respectively. To investigate the mechanistic regulation of this process, we applied an unbiased, quantitative, single-cell-resolution image analysis pipeline to analyze embryos lacking or exhibiting reduced levels of GATA6. We find that Gata6 mutants exhibit a complete absence of PrE and demonstrate that GATA6 levels regulate the timing and speed of lineage commitment within the ICM. Furthermore, we show that GATA6 is necessary for PrE specification by FGF signaling and propose a model where interactions between NANOG, GATA6, and the FGF/ERK pathway determine ICM cell fate. This study provides a framework for quantitative analyses of mammalian embryos and establishes GATA6 as a nodal point in the gene regulatory network driving ICM lineage specification. [Copyright &y& Elsevier]

Summary: How cells convert polarity cues into cell fate specification is incompletely understood. Here, we show that Wnt/β-catenin and Wnt/PCP signaling cooperate in this process in early Xenopus embryos. We find that the Wnt coreceptor Lrp6 is asymmetrically localized to the basolateral membrane in ectodermal blastomeres. Lrp6 asymmetry is controlled by Wnt/PCP signaling, indicating that this pathway regulates not only planar- but also apicobasal cell polarity. Following asymmetric cell division, Lrp6 preferentially sorts to the deep ectodermal cell layer and becomes depleted in the epithelial cell layer. This is accompanied by elevated Wnt/β-catenin signaling in deep cells, which in turn promotes their differentiation into ciliated cells. We conclude that coordinated Wnt/PCP and Wnt/β-catenin signaling convert apicobasal polarity information to specify ectodermal cell fate. [Copyright &y& Elsevier]

Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified the transcription factor Klf5 as an essential determinant of alveolar epithelial cell fate across the lifespan. We show that although dispensable for both adult alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 enforces AT1 cell lineage fidelity during development. Using infectious and non-infectious models of acute respiratory distress syndrome, we demonstrate that Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner during lung regeneration. Moreover, ex vivo organoid assays identify that Klf5 reduces AT2 cell sensitivity to inflammatory signaling to drive AT2-AT1 cell differentiation. These data define the roll of a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration. [Display omitted] • Klf5 maintains AT1 cell lineage fidelity during development • Loss of Klf5 perturbs spatiotemporal AT2 cell fate choice after acute lung injury • Klf5 represses AT2 cell sensitivity to inflammatory signaling Liberti et al. show that Klf5 is required to maintain alveolar epithelial type 1 (AT1) versus type 2 (AT2) cell fate during murine lung development. Furthermore, they demonstrate that Klf5 represses adult AT2 cell responsiveness to inflammatory signaling to inhibit proliferation and promote differentiation during lung regeneration after acute injury. [ABSTRACT FROM AUTHOR]

Summary: Stem cells possess the capacity to generate two cells of distinct fate upon division: one cell retaining stem cell identity and the other cell destined to differentiate. These cell fates are established by cell-type-specific genetic networks. To comprehensively identify components of these networks, we performed a large-scale RNAi screen in Drosophila female germline stem cells (GSCs) covering ∼25% of the genome. The screen identified 366 genes that affect GSC maintenance, differentiation, or other processes involved in oogenesis. Comparison of GSC regulators with neural stem cell self-renewal factors identifies common and cell-type-specific self-renewal genes. Importantly, we identify the histone methyltransferase Set1 as a GSC-specific self-renewal factor. Loss of Set1 in neural stem cells does not affect cell fate decisions, suggesting a differential requirement of H3K4me3 in different stem cell lineages. Altogether, our study provides a resource that will help to further dissect the networks underlying stem cell self-renewal. [ABSTRACT FROM AUTHOR]

Summary: The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver versus pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate, whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell-fate decisions and outgrowth of the embryonic endodermal anlagen. [ABSTRACT FROM AUTHOR]

Summary: Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this, we studied the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona glomerulosa (zG) and the inner zona fasciculata (zF). These layers have separate functions, are continuously renewed in response to physiological demands, and are regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship, and renewal mechanism, however, remain poorly understood. Cell-fate mapping and gene-deletion studies using zG-specific Cre expression demonstrate that differentiated zG cells undergo lineage conversion into zF cells. In addition, zG maintenance is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF-1), and zG-specific Sf-1 deletion prevents lineage conversion. These findings demonstrate that adrenocortical zonation and regeneration result from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues. [Copyright &y& Elsevier]

Summary: We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation. [ABSTRACT FROM AUTHOR]

Summary: Secreted signaling molecules typically float in the outer leaflet of the plasma membrane or freely diffuse away from the signaling cell, suggesting that a signal should be sensed equally by all neighboring cells. However, we demonstrate that Spitz (Spi)-mediated epidermal growth factor receptor (EGFR) signaling is spatially biased to selectively determine the induction of a single bract cell on the proximal side of each mechanosensory organ on the Drosophila leg. Dynamic and oriented cellular protrusions emanating from the socket cell, the source of Spi, robustly favor the Spi/EGFR signaling response in a particular cell among equally competent neighbors. We propose that these protrusive structures enhance signaling by increasing contact between the signaling and responding cells. The planar polarized direction of the protrusions determines the direction of the signaling outcome. This asymmetric cell signaling serves as a developmental mechanism to generate spatially patterned cell fates. [Copyright &y& Elsevier]

Summary: Morphogenesis is a developmental phase during which cell fates are executed. Mechanical forces shaping individual cells play a key role during tissue morphogenesis. By investigating morphogenesis of the Caenorhabditis elegans hermaphrodite vulva, we show that the force-generating actomyosin network is differentially regulated by NOTCH and EGFR/RAS/MAPK signaling to shape the vulval tube. NOTCH signaling activates expression of the RHO kinase LET-502 in the secondary cell lineage through the ETS-family transcription factor LIN-1. LET-502 induces actomyosin-mediated contraction of the apical lumen in the secondary toroids, thereby generating a dorsal pushing force. In contrast, MAPK signaling in the primary lineage downregulates LET-502 RHO kinase expression to prevent toroid contraction and allow the gonadal anchor cell to expand the dorsal lumen of the primary toroids. The antagonistic action of the MAPK and NOTCH pathways thus controls vulval tube morphogenesis linking cell fate specification to morphogenesis. [Copyright &y& Elsevier]

Summary: Patterning the Drosophila retina for color vision relies on postmitotic specification of photoreceptor subtypes. R8 photoreceptors express one of two light-sensing Rhodopsins, Rh5 or Rh6. This fate decision involves a bistable feedback loop between Melted, a PH-domain protein, and Warts, a kinase in the Hippo growth pathway. Here, we show that a subset of the Hippo pathway—Merlin, Kibra, and Lethal(2)giant larvae (Lgl), but not Expanded or Fat—is required for Warts expression and activity in R8 to specify Rh6 fate. Melted represses warts transcription to disrupt Hippo pathway activity and specify Rh5 fate. Therefore, R8 Hippo signaling exhibits ON-or-OFF regulation, promoting mutually exclusive fates. Furthermore, Merlin and Lgl are continuously required to maintain R8 neuronal subtypes. These results reveal roles for Merlin, Kibra, and Lgl in neuronal specification and maintenance and show that the Hippo pathway is reimplemented for sensory neuron fate by combining canonical and noncanonical regulatory steps. [ABSTRACT FROM AUTHOR]

Summary: We use transposon-based clonal analysis to identify the lineage classes that make the adult zebrafish caudal fin. We identify nine distinct lineage classes, including epidermis, melanocyte/xanthophore, iridophore, intraray glia, lateral line, osteoblast, dermal fibroblast, vascular endothelium, and resident blood. These lineage classes argue for distinct progenitors, or organ founding stem cells (FSCs), for each lineage, which retain fate restriction throughout growth of the fin. Thus, distinct FSCs exist for the four neuroectoderm lineages, and dermal fibroblasts are not progenitors for fin ray osteoblasts; however, artery and vein cells derive from a shared lineage in the fin. Transdifferentiation of cells or lineages in the regeneration blastema is often postulated. However, our studies of single progenitors or FSCs reveal no transfating or transdifferentiation between these lineages in the regenerating fin. This result shows that, the same as in growth, lineages retain fate restriction when passed through the regeneration blastema. [ABSTRACT FROM AUTHOR]

Summary: Changes in gene expression are thought to be important for morphological evolution, though little is known about the nature or magnitude of the differences. Here, we examine Xenopus laevis and Xenopus tropicalis, two amphibians with very similar development, and ask how their transcriptomes compare. Despite separation for ∼30–90 million years, there is strong conservation in gene expression in the vast majority of the expressed orthologs. Significant changes occur in the level of gene expression but changes in the timing of expression (heterochrony) were much less common. Differences in level were concentrated in the earliest embryonic stages. Changes in timing were prominently found in pathways that respond to selective features of the environment. We propose that different evolutionary rates across developmental stages may be explained by the stabilization of cell fate determination in the later stages. [Copyright &y& Elsevier]

Summary: An important step in early embryonic development is the allocation and segregation of germ layer fates into distinct embryonic regions. However, the mechanism that segregates the mesendoderm into mesoderm and endoderm fates remains largely unknown in most animals. Here, using ascidians, a primitive chordate, we show that these fates are segregated by partitioning of asymmetrically localized Not mRNA from the mesendoderm cell to its mesodermal daughter. Migration of the mesendoderm cell nucleus to the future mesoderm-forming region, release of Not mRNA from the nucleus, Wnt5α-dependent local retention of the mRNA, and subsequent repositioning of the mitotic spindle to the center of the cell are each required for the asymmetric localization and partitioning of Not mRNA. Our results show that nuclear migration plays an unexpected role in asymmetric cell divisions that segregate germ layer fates in chordate embryos. [ABSTRACT FROM AUTHOR]

Summary: Sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. Previous studies have established that retinoic acid (RA) triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis, whereas in the developing testis, the enzyme CYP26B1 degrades RA and germ cells are not induced to enter meiosis. Using in vitro and in vivo models, we demonstrate that fibroblast growth factor 9 (FGF9) produced in the fetal testis acts directly on germ cells to inhibit meiosis; in addition, FGF9 maintains expression of pluripotency-related genes and upregulates markers associated with male germ cell fate. We conclude that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors. [Copyright &y& Elsevier]

Summary: In all metazoan organisms, the diversification of cell types involves determination of cell fates and subsequent execution of specific differentiation programs. During Drosophila myogenesis, identity genes specify the fates of founder myoblasts, from which derive all individual larval muscles. Here, to understand how cell fate information residing within founders is translated during differentiation, we focus on three identity genes, eve, lb, and slou, and how they control the size of individual muscles by regulating the number of fusion events. They achieve this by setting expression levels of Mp20, Pax, and mspo, three genes that regulate actin dynamics and cell adhesion and, as we show here, modulate the fusion process in a muscle-specific manner. Thus, these data show how the identity information implemented by transcription factors is translated via target genes into cell-type-specific programs of differentiation. [ABSTRACT FROM AUTHOR]

Summary: The two first cell fate decisions taken in the mammalian embryo generate three distinct cell lineages: one embryonic, the epiblast, and two extraembryonic, the trophoblast and primitive endoderm. miRNAs are essential for early development, but it is not known if they are utilized in the same way in these three lineages. We find that in the pluripotent epiblast they inhibit apoptosis by blocking the expression of the proapoptotic protein Bcl2l11 (Bim) but play little role in the initiation of gastrulation. In contrast, in the trophectoderm, miRNAs maintain the trophoblast stem cell compartment by directly inhibiting expression of Cdkn1a (p21) and Cdkn1c (p57), and in the primitive endoderm, they prevent differentiation by maintaining ERK1/2 phosphorylation through blocking the expression of Mapk inhibitors. Therefore, we show that there are fundamental differences in how stem cells maintain their developmental potential in embryonic and extraembryonic tissues through miRNAs. [ABSTRACT FROM AUTHOR]

Summary: Three distinct cell types are present within the 64-cell stage mouse blastocyst. We have investigated cellular development up to this stage using single-cell expression analysis of more than 500 cells. The 48 genes analyzed were selected in part based on a whole-embryo analysis of more than 800 transcription factors. We show that in the morula, blastomeres coexpress transcription factors specific to different lineages, but by the 64-cell stage three cell types can be clearly distinguished according to their quantitative expression profiles. We identify Id2 and Sox2 as the earliest markers of outer and inner cells, respectively. This is followed by an inverse correlation in expression for the receptor-ligand pair Fgfr2/Fgf4 in the early inner cell mass. Position and signaling events appear to precede the maturation of the transcriptional program. These results illustrate the power of single-cell expression analysis to provide insight into developmental mechanisms. The technique should be widely applicable to other biological systems. [Copyright &y& Elsevier]

Summary: Cell fate determination during developmental patterning is often controlled by concentration gradients of morphogens. In the epithelial field, morphogens like the Hedgehog (Hh) peptides diffuse both apically and basolaterally; however, whether both pools of Hh are sensed at the cellular level is unclear. Here, we show that interfering with the amount of apical Hh causes a dramatic change in the long-range activation of low-threshold Hh target genes, without similar effect on short-range, high-threshold targets. We provide genetic evidence that the glypican Dally upregulates apical Hh levels, and that the release of Dally by the hydrolase Notum promotes apical Hh long-range activity. Our data suggest that several pools of Hh are perceived in epithelial tissues. Thus, we propose that the overall gradient of Hh is a composite of pools secreted by different routes (apical and basolateral), and that a cellular summation of these components is required for appropriate developmental patterning. [Copyright &y& Elsevier]

Summary: Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates β-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces β-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates β-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number. [Copyright &y& Elsevier]

Summary: Typical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis. [Copyright &y& Elsevier]

Summary: NAD(H)-binding proteins play important roles in cell-cycle and developmental signaling in eukaryotes. We identified a bifunctional NAD(H)-binding regulator (KidO) that integrates cell-fate signaling with cytokinesis in the bacterium Caulobacter crescentus. KidO stimulates the DivJ kinase and directly acts on the cytokinetic tubulin, FtsZ, to tune cytokinesis with the cell cycle. At the G1→S transition, DivJ concomitantly signals the ClpXP-dependent degradation of KidO and CtrA, a cell-cycle transcriptional regulator/DNA replication inhibitor. This proteolytic event directs KidO and CtrA into oscillatory cell-cycle abundance patterns that coordinately license replication and cytokinesis. KidO resembles NAD(P)H-dependent oxidoreductases, and conserved residues in the KidO NAD(H)-binding pocket are critical for regulation of FtsZ, but not for DivJ. Since NADPH-dependent regulation by a KidO-like oxidoreductase also occurs in humans, organisms from two domains of life exploit the enzymatic fold of an ancestral oxidoreductase potentially to coordinate cellular or developmental activities with the availability of the metabolic currency, NAD(P)H. [Copyright &y& Elsevier]

To defend against pathogens, activated immune cells must rapidly produce diverse lymphocyte subtypes. In a recent report in Nature , Verbist et al. (2016) describe how a regulatory loop acting between metabolic and transcriptional programs, centered around the asymmetric cell division machinery and the proto-oncogene c-Myc, establishes distinct T cell fates. [ABSTRACT FROM AUTHOR]

Summary: Maintenance of multipotency and how cells exit this state to adopt a specific fate are central questions in stem cell biology. During vertebrate development, multipotent cells of the dorsal somite, the dermomyotome, give rise to different lineages such as vascular smooth and skeletal muscle, regulated by the transcription factors Foxc2 and Pax3, respectively. Here we show reciprocal inhibition between Pax3 and Foxc2 in the mouse embryo. Using both genetic approaches and manipulation of external signals in somite explants, we demonstrate that the Pax3:Foxc2 ratio modulates myogenic versus vascular cell fates. This provides insight into how cell fate choices are orchestrated by these lineage genes in the dermomyotome. [Copyright &y& Elsevier]

Summary: Epigenetic mechanisms set apart the active and inactive regions in the genome of multicellular organisms to produce distinct cell fates during embryogenesis. Here, we report on the epigenetic and transcriptome genome-wide maps of gastrula-stage Xenopus tropicalis embryos using massive parallel sequencing of cDNA (RNA-seq) and DNA obtained by chromatin immunoprecipitation (ChIP-seq) of histone H3 K4 and K27 trimethylation and RNA Polymerase II (RNAPII). These maps identify promoters and transcribed regions. Strikingly, genomic regions featuring opposing histone modifications are mostly transcribed, reflecting spatially regulated expression rather than bivalency as determined by expression profile analyses, sequential ChIP, and ChIP-seq on dissected embryos. Spatial differences in H3K27me3 deposition are predictive of localized gene expression. Moreover, the appearance of H3K4me3 coincides with zygotic gene activation, whereas H3K27me3 is predominantly deposited upon subsequent spatial restriction or repression of transcriptional regulators. These results reveal a hierarchy in the spatial control of zygotic gene activation. [Copyright &y& Elsevier]

Summary: Clonal lineage information is fundamental in revealing cell fate choices. Using genetic single-cell labeling in utero, we investigated lineage segregations during anteroposterior axis formation in mouse. We show that while endoderm and surface ectoderm segregate during gastrulation, neural ectoderm and mesoderm share a common progenitor persisting through all stages of axis elongation. These data challenge the paradigm that the three germ layers, formed by gastrulation, constitute the primary branchpoints in differentiation of the pluripotent epiblast toward tissue-specific precursors. Bipotent neuromesodermal progenitors show self-renewing characteristics and may represent the cellular substrate coupling sustained axial elongation and coordinated differentiation of these tissues. These findings have important implications for the interpretation of the phenotypic defects of several mouse mutants and the directed differentiation of embryonic stem (ES) cells in vitro. [Copyright &y& Elsevier]

Summary: Vertebrate hematopoiesis first produces primitive (embryonic) lineages and ultimately generates the definitive (adult) blood. Whereas definitive hematopoiesis may produce many diverse blood types via a common multipotent progenitor, primitive hematopoiesis has been thought to produce only erythrocytes or macrophages via progenitors that are unipotent for single blood lineages. Using a variety of in vivo cell-tracing techniques, we show that primitive blood in zebrafish derives from two different progenitor types. On the dorsal gastrula, blood progenitors are unipotential cells that divide infrequently, populate the rostral blood islands, and differentiate into macrophages. In contrast, on the ventral gastrula, blood progenitors are multipotential cells with rapid cell cycles; populate the intermediate cell mass; and differentiate into erythrocytes, neutrophils, and thrombocytes. Our results demonstrate the existence of primitive hematopoietic progenitors that are segregated very early in development and that are specified to produce either a unipotent or a multipotent blood cell lineage. [Copyright &y& Elsevier]

Summary: During embryogenesis, organ development is dependent upon maintaining appropriate progenitor cell commitment. Synovial joints develop from a pool of progenitor cells that differentiate into various cell types constituting the mature joint. The involvement of the musculature in joint formation has long been recognized. However, the mechanism by which the musculature regulates joint formation has remained elusive. In this study, we demonstrate, utilizing various murine models devoid of limb musculature or its contraction, that the contracting musculature is fundamental in maintaining joint progenitors committed to their fate, a requirement for correct joint cavitation and morphogenesis. Furthermore, contraction-dependent activation of β-catenin, a key modulator of joint formation, provides a molecular mechanism for this regulation. In conclusion, our findings provide the missing link between progenitor cell fate determination and embryonic movement, two processes shown to be essential for correct organogenesis. [Copyright &y& Elsevier]

Summary: The organ of Corti, the auditory organ of the inner ear, contains two types of sensory hair cells and at least seven types of supporting cells. Most of these supporting cell types rely on Notch-dependent expression of Hes/Hey transcription factors to maintain the supporting cell fate. Here, we show that Notch signaling is not necessary for the differentiation and maintenance of pillar cell fate, that pillar cells are distinguished by Hey2 expression, and that—unlike other Hes/Hey factors—Hey2 expression is Notch independent. Hey2 is activated by FGF and blocks hair cell differentiation, whereas mutation of Hey2 leaves pillar cells sensitive to the loss of Notch signaling and allows them to differentiate as hair cells. We speculate that co-option of FGF signaling to render Hey2 Notch independent also liberated pillar cells from the need for direct contact with surrounding hair cells, and enabled evolutionary remodeling of the complex cellular mosaic of the inner ear. [Copyright &y& Elsevier]

Summary: Although FoxO and Pax proteins represent two important families of transcription factors in determining cell fate, they had not been functionally or physically linked together in mediating regulation of a common target gene during normal cellular transcription programs. Here, we identify MyoD, a key regulator of myogenesis, as a direct target of FoxO3 and Pax3/7 in myoblasts. Our cell-based assays and in vitro studies reveal a tight codependent partnership between FoxO3 and Pax3/7 to coordinately recruit RNA polymerase II and form a preinitiation complex (PIC) to activate MyoD transcription in myoblasts. The role of FoxO3 in regulating muscle differentiation is confirmed in vivo by observed defects in muscle regeneration caused by MyoD downregulation in FoxO3 null mice. These data establish a mutual interdependence and functional link between two families of transcription activators serving as potential signaling sensors and regulators of cell fate commitment in directing tissue specific MyoD transcription. [Copyright &y& Elsevier]

Summary: Wnt signaling regulates a variety of developmental processes in animals. Although the β-catenin-dependent (canonical) pathway is known to control cell fate, a similar role for noncanonical Wnt signaling has not been established in mammals. Moreover, the intracellular cascades for noncanonical Wnt signaling remain to be elucidated. Here, we delineate a pathway in which Wnt3a signals through the Gαq/11 subunits of G proteins to activate phosphatidylinositol signaling and PKCδ in the murine ST2 cells. Gαq/11-PKCδ signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCδ homozygous mutant mice exhibit a deficit in embryonic bone formation. Furthermore, Wnt7b, expressed by osteogenic cells in vivo, induces osteoblast differentiation in vitro via the PKCδ-mediated pathway; ablation of Wnt7b in skeletal progenitors results in less bone in the mouse embryo. Together, these results reveal a Wnt-dependent osteogenic mechanism, and they provide a potential target pathway for designing therapeutics to promote bone formation. [Copyright &y& Elsevier]

Hallmark mutations in WNT and SHH medulloblastoma are usually distinct, but DDX3X is often mutated in both subgroups. In this issue of Developmental Cell , Patmore et al. identify Ddx3x as essential for hindbrain patterning, cell fate determination, and as a tumor suppressor gene that restricts cell lineage progression in tumorigenesis. Hallmark mutations in WNT and SHH medulloblastoma are usually distinct, but DDX3X is often mutated in both subtypes. In this issue of Developmental Cell , Patmore et al. identify Ddx3x as essential for hindbrain patterning, cell fate determination, and as a tumor suppressor gene that restricts cell lineage progression in tumorigenesis. [ABSTRACT FROM AUTHOR]

Summary: Shh-Gli signaling controls cell fates in the developing ventral neural tube by regulating the patterned expression of transcription factors in neural progenitors. However, the molecular mechanisms that limit target gene responses to specific domains are unclear. Here, we show that Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its restricted expression in the ventral spinal cord. Identification and characterization of an Nkx2.2 enhancer reveals that expression is directly regulated by positive Shh-Gli signaling and negative Tcf repressor activity. Our data indicate that the dorsal limit of Nkx2.2 is controlled by Tcf4-mediated transcriptional repression, and not by a direct requirement for high-level Shh-Gli signaling, arguing against a simple model based on differential Gli factor affinities in target genes. These results identify a transcriptional mechanism that integrates graded Shh and Wnt signaling to define progenitor gene expression domains and cell fates in the neural tube. [Copyright &y& Elsevier]

Summary: In Caenorhabditis elegans, heterochronic genes constitute a developmental timer that specifies temporal cell fate selection. The heterochronic gene lin-42 is the C. elegans homolog of Drosophila and mammalian period, key regulators of circadian rhythms, which specify changes in behavior and physiology over a 24 hr day/night cycle. We show a role for two other circadian gene homologs, tim-1 and kin-20, in the developmental timer. Along with lin-42, tim-1 and kin-20, the C. elegans homologs of the Drosophila circadian clock genes timeless and doubletime, respectively, are required to maintain late-larval identity and prevent premature expression of adult cell fates. The molecular parallels between circadian and developmental timing pathways suggest the existence of a conserved molecular mechanism that may be used for different types of biological timing. [Copyright &y& Elsevier]

Summary: Notch signaling controls numerous cell fate decisions during animal development. These typically involve a Notch-mediated switch in transcription of target genes, although the details of this molecular mechanism are poorly understood. Here, we identify dBre1 as a nuclear component required cell autonomously for the expression of Notch target genes in Drosophila development. dBre1 affects the levels of Su(H) in imaginal disc cells, and it stimulates the Su(H)-mediated transcription of a Notch-specific reporter in transfected Drosophila cells. Strikingly, dBre1 mutant clones show much reduced levels of methylated lysine 4 on histone 3 (H3K4m), a chromatin mark that has been implicated in transcriptional activation. Thus, dBre1 is the functional homolog of yeast Bre1p, an E3 ubiquitin ligase required for the monoubiquitination of histone H2B and, indirectly, for H3K4 methylation. Our results indicate that histone modification is critical for the transcription of Notch target genes. [Copyright &y& Elsevier]

In Drosophila, commitment of a cell to a sense organ precursor (SOP) fate requires bHLH proneural transcription factor upregulation, a process that depends in most cases on the interplay of proneural gene autoregulation and inhibitory Notch signaling. A subset of SOPs are selected by a recruitment pathway involving EGFR signaling to ectodermal cells expressing the proneural gene atonal. We show that EGFR signaling drives recruitment by directly facilitating atonal autoregulation. Pointed, the transcription factor that mediates EGFR signaling, and Atonal protein itself bind cooperatively to adjacent conserved binding sites in an atonal enhancer. Recruitment is therefore contingent on the combined presence of Atonal protein (providing competence) and EGFR signaling (triggering recruitment). Thus, autoregulation is the nodal control point targeted by signaling. This exemplifies a simple and general mechanism for regulating the transition from competence to cell fate commitment whereby a cell signal directly targets the autoregulation of a selector gene. [Copyright &y& Elsevier]

Cell fate diversity can be achieved through the asymmetric segregation of cell fate determinants. In the Drosophila embryo, neuroblasts divide asymmetrically and in a stem cell fashion. The determinants Prospero and Numb localize in a basal crescent and are partitioned from neuroblasts to their daughters (GMCs). Here we show that nonmuscle myosin II regulates asymmetric cell division by an unexpected mechanism, excluding determinants from the apical cortex. Myosin II is activated by Rho kinase and restricted to the apical cortex by the tumor suppressor Lethal (2) giant larvae. During prophase and metaphase, myosin II prevents determinants from localizing apically. At anaphase and telophase, myosin II moves to the cleavage furrow and appears to “push” rather than carry determinants into the GMC. Therefore, the movement of myosin II to the contractile ring not only initiates cytokinesis but also completes the partitioning of cell fate determinants from the neuroblast to its daughter. [Copyright &y& Elsevier]

We have studied the role of Notch-1 and its antagonist Numb in the activation of satellite cells during postnatal myogenesis. Activation of Notch-1 promoted the proliferation of myogenic precursor cells expressing the premyoblast marker Pax3. Attenuation of Notch signaling by increases in Numb expression led to the commitment of progenitor cells to the myoblast cell fate and the expression of myogenic regulatory factors, desmin, and Pax7. In many intermediate progenitor cells, Numb was localized asymmetrically in actively dividing cells, suggesting an asymmetric cell division and divergent cell fates of daughter cells. The results indicate that satellite cell activation results in a heterogeneous population of precursor cells with respect to Notch-1 activity and that the balance between Notch-1 and Numb controls cellular homeostasis and cell fate determination. [Copyright &y& Elsevier]