Math5 is required for both early retinal neuron differentiation and cell cycle progression

Le, Tien; Wroblewski, Emily E.; Patel, S.; Riesenberg, Amy N.; Brown, Nadean L.

doi:10.1016/j.ydbio.2006.03.055

Cited by 96 publications

(139 citation statements)

References 84 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…Atoh7 is expressed while the retinal progenitor cells are still dividing. Although Atoh7 has been suggested to promote cell-cycle exit, it has not been unequivocally demonstrated to mark the last cell cycle (16,39). Pou4f2 and Isl1 are expressed largely in postmitotic RGCs, although their expression can be initiated during the S phase of the last cell division (40,41).…”

Section: Resultsmentioning

confidence: 99%

“…Pou4f2 and Isl1 are expressed largely in postmitotic RGCs, although their expression can be initiated during the S phase of the last cell division (40,41). Cells normally expressing Atoh7 in the Atoh7-null retina experience a transient pause in cell-cycle progression but will continue to divide (17,39). Thus it is not clear whether Pou4f2 and Isl1 play any roles in the cell-cycle exit during RGC development.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Studies of neurogenesis in Drosophila demonstrate that Delta is regulated by proneural bHLH transcription factors such as acheate-scute or atonal (reviewed by Skeath and Carroll, 1994;Bertrand et al, 2002). Many bHLH homologs are expressed in the vertebrate retina, but only Ascl1 and Neurog2 are expressed in mitotically active progenitors (Jasoni et al, 1994;Jasoni and Reh, 1996;Perron et al, 1998;Yan et al, 2001;Marquardt, et al, 2001;Ma and Wang, 2006;Le et al, 2006;Nelson and Reh, 2008). While the functions of proneural bHLH genes have been extensively investigated with respect to their role in retinal cell fate specification (reviewed by Cepko, 1999;Vetter and Brown, 2001;Yan et al, 2005;Ohsawa and Kageyama, 2007;Harada et al, 2007), their function in the regulation Notch ligands have not been described in the developing retina.…”

Section: Conserved Ascl1/delta-like/notch/hes Molecular Circuitry In mentioning

confidence: 99%

Acheate‐scute like 1 (Ascl1) is required for normal delta‐like (Dll) gene expression and notch signaling during retinal development

Nelson

Hartman

Ray

et al. 2009

Developmental Dynamics

View full text Add to dashboard Cite

SummaryDelta gene expression in Drosophila is regulated by proneural bHLH transcription factors, such as acheate-scute. In vertebrates, multiple Delta-like and proneural bHLH genes are expressed during neurogenesis, especially in the retina. We recently uncovered a relationship between Acheatescute like 1 (Ascl1), Delta-like genes, and Notch in chick retinal progenitors. Here, we report that mammalian retinal progenitors are also the primary source of Delta-like genes, likely signaling through Notch among themselves, while differentiating neurons expressed Jagged2. Ascl1 is coexpressed in Delta-like and Notch active progenitors, and required for normal Delta-like gene expression and Notch signaling. We also reveal a role for Ascl1 in the regulation of Hes6, a proneurogenic factor that inhibits Notch signaling to promote neural rather than glial differentiation. Thus, these results suggest a molecular mechanism whereby attenuated Notch levels coupled with reduced proneurogenic activity in progenitors leads to increased gliogenesis and decreased neurogenesis in the Ascl1 deficient retina.

show abstract

“…Although Math5 mRNA is only expressed by retinal progenitors that are becoming terminally mitotic (Le et al, 2006), Math5-GFP purdures longer, like Math5 LacZ (Brown et al, 2001). As a consequence, differentiated RGCs express GFP throughout their nucleus and cytoplasm, and along the length of their axons.…”

Section: Math5-gfp Expression In the Developing Visual Systemmentioning

confidence: 99%

“…In the absence of Math5 RGCs fail to form, and although the eyes appear normal externally, these mice completely lack optic nerves (Brown et al, 2001;Wang et al, 2001). Math5 expression is also critical for the timing of RGC differentiation; in its absence this temporal window is shifted such that these cells adopt late fates, predominantly Müller glia (Brzezinski, 2005;Le et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Conserved regulation of Math5 and Math1 revealed by Math5-GFP transgenes

Hufnagel

Riesenberg

Saul

et al. 2007

Molecular and Cellular Neuroscience

Self Cite

View full text Add to dashboard Cite

Retinal ganglion cell genesis requires the proneural bHLH transcription factor Math5 (Atoh7), but little is known about the regulatory elements that control its expression. Here, we investigate Math5 gene regulation using transgenic mice. These mice express GFP in the prenatal retina, livelabeling RGC axon migration and innervation of the brain. Unexpectedly, these Math5-GFP transgenes are also found in Math1 expression domains throughout the nervous system, intriguing since Math5 and Math1 normally exhibit nonoverlapping expression. Furthermore, Math5-GFP and Math1 are regulated similarly, by both Pax6 and Math1 itself, in the lower rhombic lip and dorsal spinal cord. We also show that Pax6 binds to particular Math5 and Math1 regulatory sequences in vitro. Together these data suggest that these atonal semi-orthologues may share conserved regulatory elements that are normally silent in the Math5 gene.

show abstract

Math5 is required for both early retinal neuron differentiation and cell cycle progression

Cited by 96 publications

References 84 publications

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

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

Acheate‐scute like 1 (Ascl1) is required for normal delta‐like (Dll) gene expression and notch signaling during retinal development

Conserved regulation of Math5 and Math1 revealed by Math5-GFP transgenes

Contact Info

Product

Resources

About