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Abstract Background Spiders evolved different types of eyes, a pair of primary eyes that are usually forward pointing, and three pairs of secondary eyes that are typically situated more posterior and lateral on the spider’s head. The best understanding of arthropod eye development comes from the vinegar fly Drosophila melanogaster, the main arthropod model organism, that also evolved different types of eyes, the larval eyes and the ocelli and compound eyes of the imago. The gene regulatory networks that underlie eye development in this species are well investigated revealing a conserved core network, but also show several differences between the different types of eyes. Recent candidate gene approaches identified a number of conserved genes in arthropod eye development, but also revealed crucial differences including the apparent lack of some key factors in some groups of arthropods, including spiders. Results Here, we re-analysed our published scRNA sequencing data and found potential key regulators of spider eye development that were previously overlooked. Unlike earlier research on this topic, our new data suggest that Hedgehog (Hh)-signalling is involved in eye development in the spider Parasteatoda tepidariorum. By investigating embryonic gene expression in representatives of all main groups of spiders, we demonstrate that this involvement is conserved in spiders. Additionally, we identified genes that are expressed in the developing eyes of spiders, but that have not been studied in this context before. Conclusion Our data show that single-cell sequencing represents a powerful method to gain deeper insight into gene regulatory networks that underlie the development of lineage-specific organs such as the derived set of eyes in spiders. Overall, we gained deeper insight into spider eye development, as well as the evolution of arthropod visual system formation.

Background: Spiders evolved different types of eyes, a pair of primary eyes that are usually forward pointing, and three pairs of secondary eyes that are typically situated more posterior and lateral on the spider's head. The best understanding of arthropod eye development comes from the vinegar fly Drosophila melanogaster, the main arthropod model organism, that also evolved different types of eyes, the larval eyes and the ocelli and compound eyes of the imago. The gene regulatory networks that underlie eye development in this species are well investigated revealing a conserved core network, but also show several differences between the different types of eyes. Recent candidate gene approaches identified a number of conserved genes in arthropod eye development, but also revealed crucial differences including the apparent lack of some key factors in some groups of arthropods, including spiders. Results: Here, we re-analysed our published scRNA sequencing data and found potential key regulators of spider eye development that were previously overlooked. Unlike earlier research on this topic, our new data suggest that Hedgehog (Hh)-signalling is involved in eye development in the spider Parasteatoda tepidariorum. By investigating embryonic gene expression in representatives of all main groups of spiders, we demonstrate that this involvement is conserved in spiders. Additionally, we identified genes that are expressed in the developing eyes of spiders, but that have not been studied in this context before. Conclusion: Our data show that single-cell sequencing represents a powerful method to gain deeper insight into gene regulatory networks that underlie the development of lineage-specific organs such as the derived set of eyes in spiders. Overall, we gained deeper insight into spider eye development, as well as the evolution of arthropod visual system formation. [ABSTRACT FROM AUTHOR]

Stereotyped synaptic connections define the neural circuits of the brain. In vertebrates, stimulus-independent activity contributes to neural circuit formation. It is unknown whether this type of activity is a general feature of nervous system development. Here, we report patterned, stimulus-independent neural activity in the Drosophila visual system during synaptogenesis. Using in vivo calcium, voltage, and glutamate imaging, we found that all neurons participate in this spontaneous activity, which is characterized by brain-wide periodic active and silent phases. Glia are active in a complementary pattern. Each of the 15 of over 100 specific neuron types in the fly visual system examined exhibited a unique activity signature. The activity of neurons that are synaptic partners in the adult was highly correlated during development. We propose that this cell-type-specific activity coordinates the development of the functional circuitry of the adult brain.

Astonishing functional diversity exists among arthropod eyes, yet eye development relies on deeply conserved genes. This phenomenon is best understood for early events, whereas fewer investigations have focused on the influence of later transcriptional regulators on diverse eye organizations and the contribution of critical support cells, such as Semper cells (SCs). As SCs in Drosophila melanogaster secrete the lens and function as glia, they are critical components of ommatidia. Here, we perform RNAi-based knockdowns of the transcription factor cut (CUX in vertebrates), a marker of SCs, the function of which has remained untested in these cell types. To probe for the conserved roles of cut, we investigate two optically different compound eyes: the apposition optics of D. melanogaster and the superposition optics of the diving beetle Thermonectus marmoratus. In both cases, we find that multiple aspects of ocular formation are disrupted, including lens facet organization and optics as well as photoreceptor morphogenesis. Together, our findings support the possibility of a generalized role for SCs in arthropod ommatidial form and function and introduces Cut as a central player in mediating this role.

In the retinocollicular projection, the axons from functionally distinct retinal ganglion cell (RGC) types form synapses in a stereotypical manner along the superficial to deep axis of the superior colliculus (SC). Each lamina contains an orderly topographic map of the visual scene but different laminae receive inputs from distinct sets of RGCs, and inputs to each lamina are aligned with the others to integrate parallel streams of visual information. To determine the relationship between laminar organization and topography of physiologically defined RGC types, we used genetic and anatomical axon tracing techniques in wild type and ephrin-A mutant mice. We find that adjacent RGCs of the same physiological type can send axons to both ectopic and normal topographic locations, supporting a penetrance model for ephrin-A independent mapping cues. While the overall laminar organization in the SC is unaffected in ephrin-A2/A5 double mutant mice, analysis of the laminar locations of ectopic terminations shows that the topographic maps of different RGC types are misaligned. These data lend support to the hypothesis that the retinocollicular projection is a superimposition of a number of individual two-dimensional topographic maps that originate from specific types of RGCs, require ephrin-A signaling, and form independently of the other maps.

• Coconut oil-based diet selectively reduces docosahexaenoic acid in the visual system. • Omega-3 nutritional restriction has been shown to slow down synaptic elimination in the visual system. • Docosahexaenoic acid restriction modifies microglia in number and morphology. • Nutritional restriction of omega-3 disturbs the pattern of cytokine expression. • A critical supplementation period rescues the effects of the coconut oil-based diet. Modern western diets have been associated with a reduced proportion of dietary omega-3 fatty acids leading to decreased levels of DHA (docosahexaenoic acid) in the brain. Low DHA content has been associated with altered development of visual acuity in infants and also with an altered time course of synapse elimination and plasticity in subcortical visual nuclei in rodents. Microglia has an active role in normal developmental processes such as circuitry refinement and plasticity, and its activation status can be modulated by omega-3 (ω3) and omega-6 (ω6) essential fatty acids. In the present study, we investigated the impact of dietary restriction of DHA (ω3−), through the chronic administration of a coconut-based diet as the only fat source. This dietary protocol resulted in a reduction in DHA content in the retina and superior colliculus (SC) and in a neuroinflammatory outcome during the development of the rodent visual system. The ω3− group showed changes in microglial morphology in the retina and SC and a corresponding altered pattern of pro-inflammatory cytokine expression. Early and late fish oil protocols supplementation were able to restore DHA levels. The early supplementation also decreased neuroinflammatory markers in the visual system. The present study indicates that a chronic dietary restriction of omega-3 fatty acids and the resulting deficits in DHA content, commonly observed in Western diets, interferes with the microglial profile leading to an inflamed microenvironment which may underlie a disruption of synapse elimination, altered topographical organization, abnormal plasticity, and duration of critical periods during brain development. [ABSTRACT FROM AUTHOR]

Hagfish eyes are markedly basic compared to the eyes of other vertebrates, lacking a pigmented epithelium, a lens and a retinal architecture built of three cell layers: the photoreceptors, interneurons and ganglion cells. Concomitant with hagfish belonging to the earliest-branching vertebrate group (the jawless Agnathans), this lack of derived characters has prompted competing interpretations that hagfish eyes represent either a transitional form in the early evolution of vertebrate vision, or a regression from a previously elaborate organ. Here, we show the hagfish retina is not extensively degenerating during its ontogeny, but instead grows throughout life via a recognizable PAX6+ ciliary marginal zone. The retina has a distinct layer of photoreceptor cells that appear to homogeneously express a single opsin of the RH1 rod opsin class. The epithelium that encompasses these photoreceptors is striking because it lacks the melanin pigment that is universally associated with animal vision; notwithstanding, we suggest this epithelium is a homologue of gnathosome retinal pigment epithelium (RPE) based on its robust expression of RPE65 and its engulfment of photoreceptor outer segments. We infer that the hagfish retina is not entirely rudimentary in its wiring, despite lacking a morphologically distinct layer of interneurons: multiple populations of cells exist in the hagfish inner retina and subsets of these express markers of vertebrate retinal interneurons. Overall, these data clarify Agnathan retinal homologies, reveal characters that now appear to be ubiquitous across the eyes of vertebrates, and refine interpretations of early vertebrate visual system evolution. [ABSTRACT FROM AUTHOR]

Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders. This article has an associated First Person interview with the first author of the paper.

Genomic instability in the central nervous system (CNS) is associated with defective neurodevelopment and neurodegeneration. Congenital human syndromes that affect the CNS development originate from mutations in genes of the DNA damage response (DDR) pathways. RINT1 (Rad50-interacting protein 1) is a partner of RAD50, that participates in the cellular responses to DNA double-strand breaks (DSB). Recently, we showed that Rint1 regulates cell survival in the developing brain and its loss led to premature lethality associated with genomic stability. To bypass the lethality of Rint1 inactivation in the embryonic brain and better understand the roles of RINT1 in CNS development, we conditionally inactivated Rint1 in retinal progenitor cells (RPCs) during embryogenesis. Rint1 loss led to accumulation of endogenous DNA damage, but RINT1 was not necessary for the cell cycle checkpoint activation in these neural progenitor cells. As a consequence, proliferating progenitors and postmitotic neurons underwent apoptosis causing defective neurogenesis of retinal ganglion cells, malformation of the optic nerve and blindness. Notably, inactivation of Trp53 prevented apoptosis of the RPCs and rescued the generation of retinal neurons and vision loss. Together, these results revealed an essential role for TRP53-mediated apoptosis in the malformations of the visual system caused by RINT1 loss and suggests that defective responses to DNA damage drive retinal malformations.

Drosophila color vision is achieved by comparing outputs from two types of color-sensitive photoreceptors, R7 and R8. Ommatidia (unit eyes) are classified into two subtypes, known as ‘pale’ or ‘yellow’, depending on Rhodopsin expression in R7 and R8. Subtype specification is controlled by a stochastic decision in R7 and instructed to the underlying R8. We find that the Activin receptor Baboon is required in R8 to receive non-redundant signaling from the three Activin ligands, activating the transcription factor dSmad2. Concomitantly, two BMP ligands activate their receptor, Thickveins, and the transcriptional effector, Mad. The Amon TGFβ processing factor appears to regulate components of the TGFβ pathway specifically in pale R7. Mad and dSmad2 cooperate to modulate the Hippo pathway kinase Warts and the growth regulator Melted; two opposing factors of a bi-stable loop regulating R8 Rhodopsin expression. Therefore, TGFβ and growth pathways interact in postmitotic cells to precisely coordinate cell-specific output.

The serotonin transporter (5-HTT) regulates serotonin homeostasis and has been used as a target for different drugs in depression treatment. Although the serotonergic system has received a lot of attention, little is known about the effects of these drugs over serotonin transporters. In this work, we investigated the expression pattern of 5-HTT during development of the visual system and the influence of fluoxetine on different signaling pathways. Our data showed that the expression of 5-HTT has a gradual increase from postnatal day 0 until 42 and decrease afterwards. Moreover, chronic fluoxetine treatment both in childhood and adolescence induces down regulation of 5-HTT expression and phosphorylation of ERK and AKT signaling pathways. Together these data suggest that the levels of 5-HTT protein could be important for the development of the central nervous system and suggest that the ERK and AKT are involved in the molecular pathways of antidepressants drugs, acting in concert to improve serotonergic signaling. [ABSTRACT FROM AUTHOR]

In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous activity and visual experience during this maturation is on-going. During development of the sensory system, the first, rough organization of connections is created by molecular factors. These connections are then modulated by the intrinsically generated activity of neurons, even before the senses have become operational. Spontaneous waves of depolarisations sweep across the nervous system, placing them in a prime position to strengthen correct connections and weaken others, shaping synapses into a useful network. A large body of work now supports the idea that, rather than being a mere side-effect of the system, spontaneous activity actually contains information which readies the nervous system so that, as soon as the senses become active, sensory information can be utilized by the animal. An example is the neonatal mouse. As soon as the eyelids first open, neurons in the cortex respond to visual information without the animal having previously encountered structured sensory input (Cang et al., 2005a; Ko et al., 2013; Rochefort et al., 2011; Zhang et al., 2012). In vivo imaging techniques have advanced considerably, allowing observation of the natural activity in the brain of living animals down to the level of the individual synapse. New (opto)genetic methods make it possible to subtly modulate the spatio-temporal properties of activity, aiding our understanding of how these characteristics relate to the function of spontaneous activity. Such experiments have had a huge impact on our knowledge by permitting direct testing of ideas about the plasticity mechanisms at play in the intact system, opening up a provocative range of fresh questions. Here, we intend to outline the most recent descriptions of spontaneous activity patterns in rodent developing sensory areas, as well as the inferences we can make about the information content of those activity patterns and ideas about the plasticity rules that allow this activity to shape the young brain.

In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous activity and visual experience during this maturation is on-going. During development of the sensory system, the first, rough organization of connections is created by molecular factors. These connections are then modulated by the intrinsically generated activity of neurons, even before the senses have become operational. Spontaneous waves of depolarizations sweep across the nervous system, placing them in a prime position to strengthen correct connections and weaken others, shaping synapses into a useful network. A large body of work now support the idea that, rather than being a mere side-effect of the system, spontaneous activity actually contains information which readies the nervous system so that, as soon as the senses become active, sensory information can be utilized by the animal. An example is the neonatal mouse. As soon as the eyelids first open, neurons in the cortex respond to visual information without the animal having previously encountered structured sensory input (Cang et al., 2005b; Rochefort et al., 2011; Zhang et al., 2012; Ko et al., 2013). In vivo imaging techniques have advanced considerably, allowing observation of the natural activity in the brain of living animals down to the level of the individual synapse. New (opto)genetic methods make it possible to subtly modulate the spatio-temporal properties of activity, aiding our understanding of how these characteristics relate to the function of spontaneous activity. Such experiments have had a huge impact on our knowledge by permitting direct testing of ideas about the plasticity mechanisms at play in the intact system, opening up a provocative range of fresh questions. Here, we intend to outline the most recent descriptions of spontaneous activity patterns in rodent developing sensory areas, as well as the inferences we can make about the information content of those activity patterns and ideas about the plasticity rules that allow this activity to shape the young brain. [ABSTRACT FROM AUTHOR]

A general property of nervous system development is that correlated activity is used to organize topographic projections. This correlated activity is typically produced by electrical coupling of adjacent neurons; however, electrical coupling is not possible for retinal ganglion cells in separate eyes that need to be precisely mapped to the same place in the brain. This forces the visual system to rely on environmental stimuli to produce the correlated activity that drives the development of binocularity, with amblyopia as necessary consequence when visual experience is abnormal. The characteristic visual deficits in both the amblyopic and the sound eyes can be understood in the context of these normal developmental processes. The auditory system provides another example--where precise connections between paired sense organs must rely on environmental stimuli for normal development--in which the analogous condition of amblyaudia occurs. [ABSTRACT FROM AUTHOR]

Astonishing functional diversity exists among arthropod eyes, yet eye development relies on deeply conserved genes. This phenomenon is best understood for early events, whereas fewer investigations have focused on the influence of later transcriptional regulators on diverse eye organizations and the contribution of critical support cells, such as Semper cells (SCs). As SCs in Drosophila melanogaster secrete the lens and function as glia, they are critical components of ommatidia. Here, we perform RNAi-based knockdowns of the transcription factor cut (CUX in vertebrates), a marker of SCs, the function of which has remained untested in these cell types. To probe for the conserved roles of cut , we investigate two optically different compound eyes: the apposition optics of D. melanogaster and the superposition optics of the diving beetle Thermonectus marmoratus . In both cases, we find that multiple aspects of ocular formation are disrupted, including lens facet organization and optics as well as photoreceptor morphogenesis. Together, our findings support the possibility of a generalized role for SCs in arthropod ommatidial form and function and introduces Cut as a central player in mediating this role., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rathore, Meece, Charlton-Perkins, Cook and Buschbeck.)

Increasing evidence shows that sensory experience is not necessary for initial patterning of neural circuitry but is essential for maintenance and plasticity. We have investigated the role of visual experience in development and plasticity of inhibitory synapses in the retinocollicular pathway of an altricial rodent, the Syrian hamster. We reported previously that visual receptive field (RF) refinement in superior colliculus (SC) occurs with the same time course in long-term dark-reared (LTDR) as in normally-reared hamsters, but RFs in LTDR animals become unrefined in adulthood. Here we provide support for the hypothesis that this failure to maintain refined RFs into adulthood results from inhibitory plasticity at both pre- and postsynaptic levels. Iontophoretic application of gabazine, a GABA receptor antagonist, or muscimol, a GABA receptor agonist, had less of an effect on RF size and excitability of adult LTDR animals than in short-term DR animals or normal animals. Consistent with these physiological observations, the percentage of GABA-immunoreactive neurons was significantly decreased in the SC of LTDR animals compared to normal animals and to animals exposed to a normal light cycle early in development, before LTDR. Thus GABAergic inhibition in the SC of LTDR animals is reduced, weakening the inhibitory surround and contributing significantly to the visual deprivation-induced enlargement of RFs seen. Our results argue that early visually-driven activity is necessary to maintain the inhibitory circuitry intrinsic to the adult SC and to protect against the consequences of visual deprivation. [ABSTRACT FROM AUTHOR]

Abstract: In the Drosophila adult visual system, photoreceptor axons and their connecting interneurons are tied into a retinotopic pattern throughout the consecutive neuropil regions: lamina, medulla and lobula complex. Lamina and medulla are joined by the first or outer optic chiasm (OOC). Medulla, lobula and lobula plate are connected by the second or inner optic chiasm (IOC). In the regulatory mutant In(1)omb H31 of the T-box gene optomotor-blind (omb), fibers were found to cross aberrantly through the IOC into the neuropil of the lobula complex. Here, we show that In(1)omb H31 causes selective loss of OMB expression from glial cells within the IOC previously identified as IOC giant glia (ICg-glia). In the absence of OMB, ICg-glia retain their glial cell identity and survive until the adult stage but tend to be displaced into the lobula complex neuropil leading to a misprojection of axons through the IOC. In addition, adult mutant glia show an aberrant increase in length and frequency of glial cell processes. We narrowed down the onset of the IOC defect to the interval between 48 h and 72 h of pupal development. Within the 40 kb of regulatory DNA lacking in In(1)omb H31 , we identified an enhancer element (ombC) with activity in the ICg-glia. ombC-driven expression of omb in ICg-glia restored proper axonal projection through the IOC in In(1)omb H31 mutant flies, as well as proper glial cell positioning and morphology. These results indicate that expression of the transcription factor OMB in ICg-glial cells is autonomously required for glial cell migration and morphology and non-autonomously influences axonal pathfinding. [Copyright &y& Elsevier]

We have developed a microscale flexible optical image projection device, integrating a matrix addressable blue/green 2-D LED array to a multicore imaging fiber. The scalable matrix addressing LED design was to enable electrical access to individual elements in the densely packed 2-D LED array. A prototype 10times10 element array was fabricated by specific device process sequence, using deep reactive ion etching and polyimide etch-back processes for device isolation and planarization. Individual elements of the array have been operated under continuous-wave current injection up to a few kiloamperes per square centimeter suggesting uncompromised performance and robustness of the planarized device structure. The device was butt-coupled to a 30 000 pixel multicore image fiber to generate a spatiotemporal pattern of light at the output end of the fiber. As application demonstrations, selected spatiotemporal patterns of illumination have been projected either to the eye of Xenopus laevis tadpoles in studies of their developing visual system, or directly to excitable neural cells in the brain. [ABSTRACT FROM PUBLISHER]

Abstract: Drosophila N-cadherin (CadN) is an evolutionarily conserved, atypical classical cadherin, which has a large complex extracellular domain and a catenin-binding cytoplasmic domain. We have previously shown that CadN regulates target selection of R7 photoreceptor axons. To determine the functional domains of CadN, we conducted a structure–function analysis focusing on its in vitro adhesive activity and in vivo function in R7 growth cones. We found that the cytoplasmic domain of CadN is largely dispensable for the targeting of R7 growth cones, and it is not essential for mediating homophilic interaction in cultured cells. Instead, the cytoplasmic domain of CadN is required for maintaining proper growth cone morphology. Domain swapping with the extracellular domain of CadN2, a related but non-adhesive cadherin, revealed that the CadN extracellular domain is required for both adhesive activity and R7 targeting. Using a target-mosaic system, we generated CadN mutant clones in the optic lobe and examined the target-selection of genetically wild-type R7 growth cones to CadN mutant target neurons. We found that CadN, but neither LAR nor Liprin-α, is required in the medulla neurons for R7 growth cones to select the correct medulla layer. Together, these data suggest that CadN mediates homophilic adhesive interactions between R7 growth cones and medulla neurons to regulate layer-specific target selection. [Copyright &y& Elsevier]

Gradients of axon guidance molecules have long been postulated to control the development of the organization of neural connections into topographic maps. We review progress in identifying molecules required for mapping and the mechanisms by which they act, focusing on the visual system, the predominant model for map development. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, remain the only molecules that meet all criteria for graded topographic guidance molecules, although others fulfill some criteria. Recent reports further define their modes of action and new roles for them, including EphB/ephrin-B control of dorsal-ventral mapping, bidirectional signaling of EphAs/ephrin-As, bifunctional action of ephrins as attractants or repellents in a context-dependent manner, and complex interactions between multiple guidance molecules. In addition, spontaneous patterned neural activity has recently been shown to be required for map refinement during a brief critical period. We speculate on additional activities required for map development and suggest a synthesis of molecular and cellular mechanisms within the context of the complexities of map development. INSETS: THE ACCESSORY OLFACTORY SYSTEM;EPH FAMILY OF RECEPTOR TYROSINE KINASES. [ABSTRACT FROM AUTHOR]

The selective elimination of axons, dendrites, axon and dendrite branches, and synapses, without loss of the parent neurons, occurs during normal development of the nervous system as well as in response to injury or disease in the adult. The widespread developmental phenomena of exuberant axonal projections and synaptic connections require both small-scale and large-scale axon pruning to generate precise adult connectivity, and they provide a mechanism for neural plasticity in the developing and adult nervous system, as well as a mechanism to evolve differences between species in a projection system. Such pruning is also required to remove axonal connections damaged in the adult, to stabilize the affected neural circuits, and to initiate their repair. Pruning occurs through either retraction or degeneration. Here we review examples of these phenomena and consider potential cellular and molecular mechanisms that underlie axon retraction and degeneration and how they might relate to each other in development and disease. [ABSTRACT FROM AUTHOR]

Rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development appreciable at behavioral, electrophysiological and molecular level. Little is known about the possible mechanisms of action through which enriched environment affects visual system development. It has been suggested that differences in maternal behavior between enriched and non-enriched conditions could contribute to the earliest effects of enriched environment on visual development and that neurotrophins, BDNF in particular, might be involved. Here, we examined Brain Derived Neurotrophic Factor (BDNF) levels in the visual cortex during development and showed that an increase occurs in the first week of life in enriched pups compared to standard reared pups; BDNF levels at birth were equal in the two groups. This suggests a postnatal rather than a prenatal effect of environment on BDNF. A detailed analysis of maternal care behavior showed that pups raised in a condition of social and physical enrichment experienced higher levels of licking behavior and physical contact compared to standard reared pups and that enhanced levels of licking were also provided to pups in an enriched environment where no adult females other than the mother were present. Thus, different levels of maternal care in different environmental conditions could act as indirect mediator for the earliest effects of enrichment on visual system development.Some of the effects of different levels of maternal care on the offspring behavior are long lasting. We measured the visual acuity of differentially reared mice at the end of the period of visual acuity development (postnatal day 45) and at 12 months of age, using a behavioral discrimination task. We found better learning abilities and higher visual acuity in enriched compared to standard reared mice at both ages. [Copyright &y& Elsevier]

In the mammalian visual system, retinal ganglion cell (RGC) projections from each eye, initially intermixed within the dorsal-lateral geniculate nucleus (dLGN), become segregated during the early stages of development, occupying distinct eye-specific layers. Electrical activity has been suggested to play a role in this process; however, the cellular mechanisms underlying eye-specific segregation are not yet defined. It is known that electrical activity is among the strongest activators of the extracellular signal-regulated kinase (ERK) pathway. Moreover, the ERK pathway is involved in the plasticity of neural connections during development. We examine the role of ERK in the segregation of retinal afferents into eye-specific layers in the dLGN. The activation of this signaling cascade was selectively blocked along the retino-thalamic circuitry by specific inhibitors, and the distribution of RGC fibers in the dLGN was studied. Our results demonstrate that the blockade of ERK signaling prevents eye-specific segregation in the dLGN, providing evidence that ERK pathway is required for the proper development of retino-geniculate connections. Of particular interest is the finding that ERK mediates this process both at the retinal and geniculate level. [ABSTRACT FROM AUTHOR]

Thus far, the developmental plasticity of the visual system has been studied by altering or reducing visual experience. Here, we investigated whether a complex sensory-motor stimulation, provided by rearing animals in an enriched environment, affects visual system development. We found that raising mice in this condition causes an earlier eye opening, a precocious development of visual acuity, and an accelerated decline of white matter-induced long-term potentiation. These effects are accompanied by a precocious cAMP response element-mediated gene expression and a significant increase of BDNF protein and GAD65/67 expression in enriched pups. In addition, we showed that enriched pups experienced higher levels of licking behavior provided by adult females. Thus, rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development as ascertained at behavioral, electrophysiological, and molecular level. [ABSTRACT FROM AUTHOR]

Occulocutaneous albinism is caused by mutations in the gene encoding the enzyme tyrosinase. Individuals with this disorder are predisposed to visual system deficits. We determined the critical period during development when tyrosinase expression is essential for the appropriate pathfinding of ganglion cell axons from the retina to the dorsal lateral geniculate nucleus. We used a line of mice with a Tyrosinase transgene, the expression of which is regulatable with the lac operator-repressor system, to restrict tyrosinase activity to discrete periods of embryogenesis. When tyrosinase was expressed throughout the period of neuroblast divisions that produce the ipsilaterally projecting ganglion cells, axonal projections innervated the same volume of the ipsilateral dorsal lateral geniculate nucleus of the thalamus as in normal mice. If tyrosinase expression ceased before the end of neuroblast divisions, or was not initiated until after they had begun, the degree of ipsilateral innervation was smaller, as in albino mice. Tyrosinase expression was not required during the entire period of pathfinding itself or during final maturation of the retinogeniculate pathway. Thus, tyrosinase appears to set up a signal early in visual system development that determines the pathway taken later by ganglion cell axons. [ABSTRACT FROM AUTHOR]

Between E15 and P4 in the hamster, axons of retinal ganglion cells in the optic tract over the dorsal lateral geniculate nucleus, are invaginated by, and make synaptic contacts with, small processes interpreted as tips or appendages of geniculate dendrites. In some cases a branch-like protrusion emerges from the axon at or close to the invagination. We hypothesize that the invaginations may be part of the mechanism by which retinocollicular axons are induced to branch and establish the retinogeniculate pathway. [ABSTRACT FROM AUTHOR]

Groups of pregnant rats were injected with two successive daily doses of H-thymidine from gestational day 12 and 13 (E12+E13) until the day before parturition (E21+22) in order to label all the multiplying precursors of neurons. At 60 days of age the proportion of neurons generated (or no longer labelled) on specific days was determined in the separate layers of the superior colliculus. Neurogenesis begins with the production of a few large multipolar neurons in layers V and IV on day E12; the bulk (87%) of these cells are generated on day E13. This early-produced band of large neurons, the intermediate magnocellular zone, divides the superior colliculus into two cytogenetically distinct regions. In both the deep and the superficial superior colliculus neuron production is relatively protracted. In the deep superior colliculus neuron production peaks on day E15 in layer VII, on day E15 and E16 in layer VI, and on day E16 (the large neurons excluded) in layer V, indicating an inside-out sequence. In the superficial superior colliculus peak production time of layer III cells is on day E15 and of layer IV cells on day E16; peak production time of both layer I and II is on day E16 but in the latter region neuron production is more prolonged and ends on day El8. One interpretation of these results is that the two pairs of superficial layers are produced in an outside-in sequence. These three cytogenetic subdivisions of the superior colliculus may be correlated with its structural-functional parcellation into an efferent spinotectal, a deep somatomotor and a superficial visual component. A comparison of neurogenesis in different components of the visuomotor and visual pathways of the rat indicates that the motor neurons of the extraocular muscles, the abducens, trochlear and oculomotor nuclei, and neurons of the nucleus of Darkschewitsch are produced first. Next in line are source neurons of efferents to the bulb and the spinal cord: those of the Edinger-Westphal nucleus and the intermediate magnocellular zone of the superior colliculus. These are followed by the relay neurons of the dorsal nucleus of the lateral geniculate body. The neurons of the superficial superior colliculus and of the visual cortex implicated in visual sensori-motor integrations are produced last. [ABSTRACT FROM AUTHOR]

Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP , are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip -deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Genomic instability in the central nervous system (CNS) is associated with defective neurodevelopment and neurodegeneration. Congenital human syndromes that affect the CNS development originate from mutations in genes of the DNA damage response (DDR) pathways. RINT1 ( Rad50-interacting protein 1 ) is a partner of RAD50, that participates in the cellular responses to DNA double-strand breaks (DSB). Recently, we showed that Rint1 regulates cell survival in the developing brain and its loss led to premature lethality associated with genomic stability. To bypass the lethality of Rint1 inactivation in the embryonic brain and better understand the roles of RINT1 in CNS development, we conditionally inactivated Rint1 in retinal progenitor cells (RPCs) during embryogenesis. Rint1 loss led to accumulation of endogenous DNA damage, but RINT1 was not necessary for the cell cycle checkpoint activation in these neural progenitor cells. As a consequence, proliferating progenitors and postmitotic neurons underwent apoptosis causing defective neurogenesis of retinal ganglion cells, malformation of the optic nerve and blindness. Notably, inactivation of Trp53 prevented apoptosis of the RPCs and rescued the generation of retinal neurons and vision loss. Together, these results revealed an essential role for TRP53-mediated apoptosis in the malformations of the visual system caused by RINT1 loss and suggests that defective responses to DNA damage drive retinal malformations., (Copyright © 2020 Gomes, Matos-Rodrigues, Frappart and Martins.)

Visual spatial perception in the mammalian brain occurs through two parallel pathways: one reaches the primary visual cortex (V1) through the thalamus and another the superior colliculus (SC) via direct projections from the retina. The origin, development, and relative function of these two evolutionarily distinct pathways remain obscure. We examined the early functional development of both pathways by simultaneously imaging pre- and post-synaptic spontaneous neuronal activity. We observed that the quality of retinal activity transfer to the thalamus and superior colliculus does not change across the first two postnatal weeks. However, beginning in the second postnatal week, retinal activity does not drive V1 as strongly as earlier wave activity, suggesting that intrinsic cortical activity competes with signals from the sensory periphery as the cortex matures. Together, these findings bring new insight into the function of the SC and V1 and the role of peripheral activity in driving both circuits across development. • Second week ("stage 3") retinal waves are very distinct from first week ("stage 2") • Stage 3 waves are especially sensitive to inhibitory blockade • Retinal influence on the colliculus and thalamus does not change over development • However, the cortex becomes relatively insensitive to retinal drive before eye opening By simultaneously measuring input activity and output activity, Gribizis et al. show that peripheral spontaneous retinal activity consistently and strongly drives response in the midbrain superior colliculus during development, while the cortex becomes progressively less sensitive to peripheral drive. [ABSTRACT FROM AUTHOR]

The compound eyes of adult stomatopod crustaceans have two to six ommatidial rows at the equator, called the midband, that are often specialized for color and polarization vision. Beneath the retina, this midband specialization is represented as enlarged optic lobe lamina cartridges and a hernia-like expansion in the medulla. We studied how the optic lobe transforms from the larvae, which possess typical crustacean larval compound eyes without a specialized midband, through metamorphosis into the adults with the midband in a two midband-row species Alima pacifica. Using histological staining, immunolabeling, and 3D reconstruction, we show that the last-stage stomatopod larvae possess double-retina eyes, in which the developing adult visual system forms adjacent to, but separate from, the larval visual system. Beneath the two retinas, the optic lobe also contains two sets of optic neuropils, comprising of a larval lamina, medulla, and lobula, as well as an adult lamina, medulla, and lobula. The larval eye and all larval optic neuropils degenerate and disappear approximately a week after metamorphosis. In stomatopods, the unique adult visual system and all optic neuropils develop alongside the larval system in the eyestalk of last-stage larvae, where two visual systems and two independent visual processing pathways coexist. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 3-14, 2018., (© 2017 Wiley Periodicals, Inc.)

Drosophila color vision is achieved by comparing outputs from two types of color-sensitive photoreceptors, R7 and R8. Ommatidia (unit eyes) are classified into two subtypes, known as 'pale' or 'yellow', depending on Rhodopsin expression in R7 and R8. Subtype specification is controlled by a stochastic decision in R7 and instructed to the underlying R8. We find that the Activin receptor Baboon is required in R8 to receive non-redundant signaling from the three Activin ligands, activating the transcription factor dSmad2. Concomitantly, two BMP ligands activate their receptor, Thickveins, and the transcriptional effector, Mad. The Amon TGFβ processing factor appears to regulate components of the TGFβ pathway specifically in pale R7. Mad and dSmad2 cooperate to modulate the Hippo pathway kinase Warts and the growth regulator Melted; two opposing factors of a bi-stable loop regulating R8 Rhodopsin expression. Therefore, TGFβ and growth pathways interact in postmitotic cells to precisely coordinate cell-specific output.

Sensitive periods and experience-dependent plasticity have become core issues in visual system development. Converging evidence indicates that visual experience is an indispensable factor in establishing mature visual system circuitry during sensitive periods and the visual system exhibits substantial plasticity while facing deprivation. The mechanisms that underlie the environmental regulation of visual system development and plasticity are of great interest but need further exploration. Here, we investigated a unique sample of human infants who experienced initial stage blindness (beginning at birth and lasting for 2-8 months) before the removal of bilateral cataracts. Retinal thickness (RT), axial length (AL), refractive status, visual grating acuity and genetic integrity were recorded during the preoperative period or at surgery and then during follow-up. The results showed that the development of the retina is malleable and associated with external environmental influences. Our work supported that the retina might play critical roles in the development of the experience-dependent visual system and its malleability might partly contribute to the sensitive period plasticity., (© 2017 The Author(s).)

Although development of the adult Drosophila compound eye is very well understood, little is known about development of photoreceptors (PRs) in the simple larval eye. We show here that the larval eye is composed of 12 PRs, four of which express blue-sensitive rhodopsin5 (rh5) while the other eight contain green-sensitive rh6. This is similar to the 30:70 ratio of adult blue and green R8 cells. However, the stochastic choice of adult color PRs and the bistable loop of the warts and melted tumor suppressor genes that unambiguously specify rh5 and rh6 in R8 PRs are not involved in specification of larval PRs. Instead, primary PR precursors signal via EGFR to surrounding tissue to develop as secondary precursors, which will become Rh6-expressing PRs. EGFR signaling is required for the survival of the Rh6 subtype. Primary precursors give rise to the Rh5 subtype. Furthermore, the combinatorial action of the transcription factors Spalt, Seven-up, and Orthodenticle specifies the two PR subtypes. Therefore, even though the larval PRs and adult R8 PRs express the same rhodopsins (rh5 and rh6), they use very distinct mechanisms for their specification. [ABSTRACT FROM AUTHOR]