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The next 50 years of developmental biology will illuminate exciting new discoveries but are also poised to provide solutions to important problems society faces. Ten scientists whose work intersects with developmental biology in various capacities tell us about their vision for the future., Competing Interests: Declaration of interests J.L. has filed patents related to printing vascularized human tissues and organs from stem cell-derived multicellular building blocks. She is a member of the scientific advisory board of Trestle Biotherapeutics, Inc. (a startup company). Trestle has also licensed IP on kidney bioprinting from Harvard, in which the author is listed as an inventor. M.S. has filed patents for reducing aneuploidy in eggs. J.H.H. was granted (through Yeda–Weizmann Institute of Science) patents relevant to the findings and technologies discussed herein (naive and naive-like pluripotency and mouse and human structure-complete embryo models [SEMs]). J.H.H. is a co-founder and chief scientific advisor of Renewal Bio, which has licensed technologies mentioned above. M.Z.G. is an inventor on patents of stem cell-derived models of human and mouse embryos. S.M. is a founder and supervisory and scientific board member of HeartBeat.bio, an IMBA spin-off, based on submitted cardioid (2020) and multi-chamber cardioid (2022) patent applications., (Copyright © 2024. Published by Elsevier Inc.)

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body., Competing Interests: Declaration of interests N.A. is the founder and CEO of Progenesis Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Early embryogenesis is a conserved and self-organized process. In the mammalian embryo, the potential for self-organization is manifested in its extraordinary developmental plasticity, allowing a correctly patterned embryo to arise despite experimental perturbation. The underlying mechanisms enabling such regulative development have long been a topic of study. In this Review, we summarize our current understanding of the self-organizing principles behind the regulative nature of the early mammalian embryo. We argue that geometrical constraints, feedback between mechanical and biochemical factors, and cellular heterogeneity are all required to ensure the developmental plasticity of mammalian embryo development., (Copyright © 2020. Published by Elsevier Inc.)

Nuclear architecture has never been carefully examined during early mammalian development at the stages leading to establishment of the embryonic and extra-embryonic lineages. Heterogeneous activity of the methyltransferase CARM1 during these stages results in differential methylation of histone H3R26 to modulate establishment of these two lineages. Here we show that CARM1 accumulates in nuclear granules at the 2- to 4-cell stage transition in the mouse embryo, with the majority corresponding to paraspeckles. The paraspeckle component Neat1 and its partner p54nrb are required for CARM1's association with paraspeckles and for H3R26 methylation. Conversely, CARM1 also influences paraspeckle organization. Depletion of Neat1 or p54nrb results in arrest at the 16- to 32-cell stage, with elevated expression of transcription factor Cdx2, promoting differentiation into the extra-embryonic lineage. This developmental arrest occurs at an earlier stage than following CARM1 depletion, indicating that paraspeckles act upstream of CARM1 but also have additional earlier roles in fate choice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The major and essential objective of pre-implantation development is to establish embryonic and extra-embryonic cell fates. To address when and how this fundamental process is initiated in mammals, we characterize transcriptomes of all individual cells throughout mouse pre-implantation development. This identifies targets of master pluripotency regulators Oct4 and Sox2 as being highly heterogeneously expressed between blastomeres of the 4-cell embryo, with Sox21 showing one of the most heterogeneous expression profiles. Live-cell tracking demonstrates that cells with decreased Sox21 yield more extra-embryonic than pluripotent progeny. Consistently, decreasing Sox21 results in premature upregulation of the differentiation regulator Cdx2, suggesting that Sox21 helps safeguard pluripotency. Furthermore, Sox21 is elevated following increased expression of the histone H3R26-methylase CARM1 and is lowered following CARM1 inhibition, indicating the importance of epigenetic regulation. Therefore, our results indicate that heterogeneous gene expression, as early as the 4-cell stage, initiates cell-fate decisions by modulating the balance of pluripotency and differentiation., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Transformation of pluripotent epiblast cells into a cup-shaped epithelium as the mouse blastocyst implants is a poorly understood and yet key developmental step. Studies of morphogenesis in embryoid bodies led to the current belief that it is programmed cell death that shapes the epiblast. However, by following embryos developing in vivo and in vitro, we demonstrate that not cell death but a previously unknown morphogenetic event transforms the amorphous epiblast into a rosette of polarized cells. This transformation requires basal membrane-stimulated integrin signaling that coordinates polarization of epiblast cells and their apical constriction, a prerequisite for lumenogenesis. We show that basal membrane function can be substituted in vitro by extracellular matrix (ECM) proteins and that ES cells can be induced to form similar polarized rosettes that initiate lumenogenesis. Together, these findings lead to a completely revised model for peri-implantation morphogenesis in which ECM triggers the self-organization of the embryo's stem cells., (Copyright © 2014 Elsevier Inc. All rights reserved.)