Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina

136

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

Section: Potential Mechanisms By Which Oc1 and Oc2 Function In Multiplementioning

confidence: 90%

mentioning

confidence: 99%

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Sapkota

Chintala

et al. 2014

136

“…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)(8)(9). RPCs are heterogeneous, as has been demonstrated by the nonuniform expression of many RPC genes (10)(11)(12)(13).…”

mentioning

confidence: 99%

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

Kaczynski

Sethuramanujam

et al. 2015

103

111

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...

“…cell culture | membrane potential | neuronal cell excitation | synaptic maturation | transcriptional regulation A large body of evidence indicates that cell type-specific transcription factors control sequential events of neuronal cell proliferation and differentiation in the early stages of developmental processes (1,2). However, how the terminal maturation processes are programmed for functional neural network formation during development remains largely to be determined.…”

mentioning

confidence: 99%

The Etv1/Er81 transcription factor orchestrates activity-dependent gene regulation in the terminal maturation program of cerebellar granule cells

Abe

Okazawa

Nakanishi

2011

In the postnatal period, cerebellar granule cells express a set of the maturation gene battery in an activity-dependent manner and establish synaptic function in the cerebellar circuitry. Using primary cultures combined with specific inhibition of signaling cascades, the present investigation revealed that the expression of the maturation genes, including the NMDA glutamate receptor NR2C and GABA A receptor GABA A Rα6 genes, is controlled by strikingly unified signaling mechanisms that operate sequentially through stimulation of AMPA and NMDA receptors, Na + channels [voltage-gated Na channel type II (Nav1.2)], and voltage-dependent Ca 2+ channels. This signaling then induces the Ets variant gene 1 (Etv1/Er81) transcription factor of the ETS family in an activity-dependent manner. Consistent with the culture study, the ChIP assay indicated that Etv1 up-regulates the maturation genes in a developmentally regulated manner. This activation, as revealed by the luciferase assay, occurrs by interacting with the Etv1-interacting motifs present in the promoter region. Importantly, in vivo knockdown of Etv1 by DNA electroporation in the developing cerebellum prevents the upregulation of the maturation genes but has no effects on preceding developmental processes occurring in the granule cells. Etv1 thus orchestrates the activity-dependent gene regulation in the terminal maturation program and specifies the identity of cerebellar granule cells.cell culture | membrane potential | neuronal cell excitation | synaptic maturation | transcriptional regulation