POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells.

Gan, Lin; Xiang, Mengqing; Zhou, Lijuan; Wagner, Daniel S.; Klein, William H.; Nathans, Jeremy

doi:10.1073/pnas.93.9.3920

Cited by 318 publications

(317 citation statements)

References 21 publications

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“…Loss-of-function and overexpression experiments revealed the crucial importance of the atonal-related transcription factors in the determination of ganglion cell fate (Brown et al, 1998;Brown et al, 2001;Kanekar et al, 1997;Ohnuma et al, 2002;Perron et al, 1999;Wang et al, 2001). Consistent with these data, Ath5 has been shown to regulate the expression of the Brn3 subfamily of POU genes, the earliest known markers of RGC differentiation, which are required for RGC development and survival (Gan et al, 1996;Hutcheson and Vetter, 2001;Liu et al, 2000;Liu et al, 2001;Perron et al, 1998;Xiang et al, 1995). Here, we confirm and extend these observations, showing that Xath3 is able to upregulate Xbrn3 genes in animal caps, suggesting that both atonal homologues can positively regulate the transcription of Brn3 genes.…”

Section: Discussionsupporting

confidence: 69%

“…Similarly, forced expression of both chick and mouse Ath5 in RPCs is able to activate cBrn3c expression (Liu et al, 2001), further corroborating the hypothesis that Brn3 genes act downstream of Ath5 to bias retinoblasts toward ganglion cell fate. However, targeted disruption of the POU gene Brn3b (Pou4f3) in the mouse does not affect retinal specification, but rather blocks terminal differentiation of a subset of RGCs, causing them to die (Gan et al, 1996;Xiang et al, 1998). This suggests that Brn3 factors may instead play a later role in differentiation and survival of subsets of RGCs.…”

Section: Introductionmentioning

confidence: 99%

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The homeobox geneXbh1cooperates with proneural genes to specify ganglion cell fate within theXenopusneural retina

et al. 2004

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Recent studies on vertebrate eye development have focused on the molecular mechanisms of specification of different retinal cell types during development. Only a limited number of genes involved in this process has been identified. In Drosophila, BarH genes are necessary for the correct specification of R1/R6 eye photoreceptors. Vertebrate Bar homologues have been identified and are expressed in vertebrate retinal ganglion cells during differentiation; however, their retinal function has not yet been addressed. In this study, we report on the role of the Xenopus Bar homologue Xbh1 in retinal ganglion cell development and its interaction with the proneural genes Xath5 and Xath3, whose ability to promote ganglion cell fate has been demonstrated. We show that XHB1 plays a crucial role in retinal cell determination, acting as a switch towards ganglion cell fate. Detailed expression analysis, animal cap assays and in vivo lipofection assays, indicate that Xbh1 acts as a late transcriptional repressor downstream of the atonal genes Xath3 and Xath5. However, the action of Xbh1 on ganglion cell development is different and more specific than that of the Xath genes, and accounts for only a part of their activities during retinogenesis.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

The homeobox geneXbh1cooperates with proneural genes to specify ganglion cell fate within theXenopusneural retina

et al. 2004

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“…S1D). In contrast, expression of brain-specific homeobox/POU domain protein 3 (Brn3), a wellcharacterized RGC marker (17), was greatly reduced during this time (Fig. S1E).…”

Section: Resultsmentioning

confidence: 85%

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

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

291

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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“…regulating two distinct but intersecting sets of downstream genes (23,(25)(26)(27)(28). More recently, we found the Pou4f2 and Isl1 form a complex to regulate their shared target genes, further demonstrating that their functions are closely linked (29).…”

mentioning

confidence: 79%

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.

103

111

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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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POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells.

Cited by 318 publications

References 21 publications

The homeobox geneXbh1cooperates with proneural genes to specify ganglion cell fate within theXenopusneural retina

The homeobox geneXbh1cooperates with proneural genes to specify ganglion cell fate within theXenopusneural retina

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

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

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