Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse

Mao, Chai An; Kiyama, Takae; Pan, Ping-Ying; Furuta, Yasuhide; Hadjantonakis, Anna-Katerina; Klein, William H.

doi:10.1242/dev.009688

Cited by 75 publications

(82 citation statements)

References 43 publications

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“…6 A-H). Tbr2 is expressed in only a subset of RGCs (20), some of which eventually become intrinsically photosensitive RGCs (ipRGCs) (21). At E14.5, we observed a near complete loss of Tbr2 expression in DKO retinas, compared with wild-type retinas in which a subset of RGCs were Tbr2 + (Fig.…”

Section: Resultsmentioning

confidence: 81%

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Sapkota

Chintala

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

122

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Previously, we have shown that Onecut1 (Oc1) and Onecut2 (Oc2) are expressed in retinal progenitor cells, developing retinal ganglion cells (RGCs), and horizontal cells (HCs). However, in Oc1-null mice, we only observed an 80% reduction in HCs, but no defects in other cell types. We postulated that the lack of defects in other cell types in Oc1-null retinas was a result of redundancy with Oc2. To test this theory, we have generated Oc2-null mice and now show that their retinas also only have defects in HCs, with a 50% reduction in their numbers. However, when both Oc1 and Oc2 are knocked out, the retinas exhibit more profound defects in the development of all early retinal cell types, including completely failed genesis of HCs, compromised generation of cones, reduced production (by 30%) of RGCs, and absence of starburst amacrine cells. Cone subtype diversification and RGC subtype composition also were affected in the double-null retina. Using RNA-Seq expression profiling, we have identified downstream genes of Oc1 and Oc2, which not only confirms the redundancy between the two factors and renders a molecular explanation for the defects in the double-null retinas, but also shows that the onecut factors suppress the production of the late cell type, rods, indicating that the two factors contribute to the competence of retinal progenitor cells for the early retinal cell fates. Our results provide insight into how onecut factors regulate the creation of cellular diversity in the retina and, by extension, in the central nervous system in general.transcription factors | neural development | retinal development | cell fate determination | gene regulation

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Section: Resultsmentioning

confidence: 81%

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Sapkota

Chintala

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

122

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“…Nevertheless, we used some of these markers to examine whether the corresponding RGC subtypes were present in the P&I EE retina. Tbr2 (also known as "Eomes") is expressed in a subset of RGCs, from which the intrinsically photosensitive RGCs (ipRGCs) arise (47)(48)(49). At E14.5, by coimmunostaining for Tbr2 and Pou4f2, we observed that Tbr2 was expressed in equivalent numbers of RGCs in the P&I EE retina and the control retina, although its expression was almost completely absent in the Atoh7 tTA/tTA retina (Fig.…”

Section: Rgcs Generated By Ectopic Pou4f2 and Isl1 Have A Largely Normalmentioning

confidence: 82%

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Kaczynski

Sethuramanujam

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

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As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors-atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)-occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.retinal development | neural development | transcription factors | cell fate specification | gene regulation A central question in neural development is how the extreme cellular diversity in the central nervous system arises from multipotent neural progenitors. The neural retina is an excellent system to address this question because of its well-defined structure and stereotypical cellular composition. The six neuronal cell types and one glial cell type (Müller glia) form a welllaminated tissue with the various types of cells positioned at distinct layers (1). Many of these cell types are composed of multiple subtypes with distinct functions (2). All cell types in the retina originate from a common pool of retinal progenitor cells (RPCs) following a distinct temporal order (3-5). The ordered births of the retinal cell types are caused by changes of competence in RPCs for the various retinal cell types (6). Both intrinsic and extrinsic mechanisms are involved in regulating the production of the various retinal cell types, but the intrinsic factors, mostly transcription factors, appear to play more deterministic roles in directing progenitor cells toward specific cell fates (5). Many such transcription factors have been identified by loss-and gain-of-function analyses, but these studies often fail to reveal the specific roles these factors play in the development of the cell types with which they are involved (7-9). RPCs are heterogeneous, as has been demonstrated by the nonuniform expression of many RPC genes (10-13). RPCs expressing specific genes, particularly those encoding transcription factors, although still multipotent, tend to be biased for certain retinal cell types. In a few cases, specific fac...

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“…Their genes are among the most downregulated in Pou4f2 null retinas as determined by microarray analysis (Qiu et al, 2008). Eomes is a T-box transcription factor that similar to Pou4f1 and 3, is expressed in developing RGCs only upon their arrival into the RGC layer (Mao et al, 2008). Its expression is directly activated by Pou4f2 through a 5' enhancer and is completely downregulated in Pou4f2 null retinas (Mao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Eomes is a T-box transcription factor that similar to Pou4f1 and 3, is expressed in developing RGCs only upon their arrival into the RGC layer (Mao et al, 2008). Its expression is directly activated by Pou4f2 through a 5' enhancer and is completely downregulated in Pou4f2 null retinas (Mao et al, 2008). Conditional inactivation of Eomes causes a 30% decrease in RGC number and optic nerve size, reduced and disorganized RGC axon myelination, and increased apoptosis (Mao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Its expression is directly activated by Pou4f2 through a 5' enhancer and is completely downregulated in Pou4f2 null retinas (Mao et al, 2008). Conditional inactivation of Eomes causes a 30% decrease in RGC number and optic nerve size, reduced and disorganized RGC axon myelination, and increased apoptosis (Mao et al, 2008). Ebf1-4 belong to a small family of HLH (helix-loop-helix) transcription factors that are selectively expressed in RGCs in mouse embryonic retinas (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Control of Retinal Ganglion Cell Specification and Differentiation

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Glaucoma - Basic and Clinical Concepts

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Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse

Cited by 75 publications

References 43 publications

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

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