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Foreword

Special issue on retinal development

In this special issue of Brain Researchwe have brought togethersome of the leading experts in the development of the visualsystem to provide their unique perspectives on the currentstatus of research in the field and important biologicalquestions for the future.

Retinal development has been extensively studied in awide variety of vertebrate species. A great deal can be learnedabout the control of retinal growth by evolutionary accounts ofthese processes, including opsin expression, developmentalregulation of eye size, and development of the fovea. Dr. Finlayhas contributed a perspective on these important and inter-esting processes. Particular emphasis is placed on thecontribution of mouse models and a web-based system forcomparing development of the retina and other regions of thecentral nervous system across species. A careful examinationof variation across species and at the individual level canprovide important insights into normal development andocular pathology.

Dr. Ashery-Padan has contributed an article discussingthe patterning and development of the optic cup duringembryogenesis, with particular emphasis on the iris of theeye. The iris develops from the boundary of the optic cup distalto the ciliary epithelium. There is also contribution from theperiocular mesenchyme. Therefore, during development theiris is formed from the same type of tissue that gives rise to thepigment epithelium, neural retina, and ciliary epithelium.Importantly, the iris retains the ability to transdifferentiateinto pigment epithelium cells and at least some cells in theneural retina and lens cells. This review by Davis-Silbermanand Ashery-Padan focuses on the anatomy, development,patterning, pathology, andmolecular pathways involved in theformation of this important ocular structure.

Cellular imaging of retinal development is a major area offuture research that is likely to have a significant impact onour understanding of the complex cellular processes that takeplace during retinogenesis. Dr. Link is one of the leadingexperts in this field and his research is focused on interkineticnuclear migration. During retinogenesis, the nuclei of theretinal progenitor cells migrate in the apical-basal directionaccording to their cell cycle phase. Following cell cycle exit,some newly postmitotic neurons migrate to their appropriate

laminar position by nuclear migration. Baye and Link reviewthe published literature on the role of interkinetic nuclearmigration in retinogenesis and present a model suggestingthat this processmay play a role in cell fate specification in thedeveloping retina.

Next, we present a series of articles on the role of extrinsiccues in retinal development. Retinal progenitor cell prolifera-tion is regulated by both extrinsic and intrinsic cues. It hasbeen well established that neurotransmitters and theirreceptors are expressed during retinal histogenesis long beforesynapses are formed. In this review by Martins and Pearson,the data suggesting that neurotransmitters regulate retinalprogenitor cell proliferation are discussed. The purinergic andmuscarinic systems promote retinal progenitor cell prolifera-tion, while the GABA and glutamate systems have theopposite effects. The temporal and spatial regulation ofneurotransmitter release and response is likely to play animportant role in the coordination of these two systems inregulating retinal progenitor cell proliferation during develop-ment. The Hedgehog signaling pathway is another importantregulator of retinal progenitor cell proliferation during verte-brate retinal development. Dr. Wallace reviews the literatureon the role of Hedgehog signaling in the developing retina.

Dr. Fischer explores the patterning of the circumferentialmarginal zone (CMZ) in the vertebrate eye in the paper by Ghaiet al. The CMZ is found in most vertebrate species, with theexception of mammals. They report that the restriction ofprogenitors in the CMZ is a gradual process during the latestages of retinal histogenesis and interestingly that thepostmitotic neurons generated from the CMZ progenitorcells remain immature for extended periods of time. Theauthors propose that the microenvironment of the CMZcontributes to this delay in the chick retina.

Several articles focus on the transcriptional networks thatare important for retinal progenitor cell proliferation and cellfate specification. bHLH family transcription factors functionas repressors and activators of key genes important for retinalcell fate specification and neuronal differentiation. Therepressor type of bHLH proteins is believed to maintain retinalprogenitor cells in an immature state, while activator bHLHproteins promote neurogenesis. Ohsawa and Kageyama

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discuss the possibility that homeodomain proteins regulatepositional identity and bHLH family members regulate thedecision to undergo neuronal cell fate specification anddifferentiation.

Chx10 and Vsx1 are the only paired-type homeodomainproteins in the mouse genome and they are both expressed inthe retina. In this research article, Clark et al. explore theregulatory interactions between these two genes. Data arepresented to suggest that Chx10 negatively regulates theexpression of Vsx1 consistent with the inverse expressionpattern in bipolar cells and in progenitor cells of Chx10-deficient retinae. Genetic epistasis studies in mice andzebrafish suggest that Vsx1 is a direct target of Chx10 anddoubly deficient retinae have a phenotype similar to that ofChx10-deficient retinae. Taken together, these data suggestthat paired-type homeodomain proteins are not essential forearly optic cup formation in vertebrates.

The transcriptional network important for photoreceptordevelopment is discussed in a review by Henning and Chen.Particular emphasis is placed on the homeodomain protein,Crx, and the other transcriptional regulatory pathways thatare important for determining photoreceptor subtype. This iscomplemented by a timely overview by Adler and Raymond ofphotoreceptor cell fate specification in humans, mice, rats,chicken, frogs, and fish. They suggest that it is premature toconclude that there is a unified model of photoreceptor cellfate specification across vertebrates.

The patterning of the retina is discussed in two articles byDrs. Schulte and Bao. The vertebrate retina exhibits aremarkable degree of neuronal patterning along its dorso-ventral and anterior-posterior axes. Two of the best-studiedpatterns in the retina are the distribution of ganglion cellsusing the retinotectal map as a readout of their patterning and

photoreceptor patterning. Importantly, photoreceptor pat-terning is species specific and may be adapted to the uniquevisual requirement for each species. In the review by Schulteand O'Brien the molecular cascades that control retinalpatterning are discussed in the context of photoreceptororganization in the vertebrate retina.

Dr. Bao explores the intraretinal patterning of retinalganglion cell axons to the optic disc. The axons must bedirected toward the center of the retina and remain in theoptic fiber layer. This process is regulated by a series ofpositive and negative cues as well as by cell adhesionmolecules. This review provides a comprehensive discussionof the regulation of axon guidance in 3-dimensional space thatserves as a model for a variety of other regions of the centralnervous system.

Finally, Dr. Pounds provides a technical report on theproper statistical analysis of retroviral lineage studies. Retro-viral lineage analysis is a powerful tool for studying retinaldevelopment and establishing the cell-autonomous roles ofdifferent genes in the developing retina. However, one of thechallenges with lineage data is the interpretation andapplication of statistical tools. In this article, we analyzedifferent types of actual data sets to emphasize the impor-tance of applying the appropriate statistical test for retinalretroviral lineage analyses.

Michael DyerE-mail address: michael.dyer@stjude.org.