Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina

Qi Zhang, Jamie Zagozewski, Shaohong Cheng, Rajiv Dixit, Shunzhen Zhang, Jimmy de Melo, Xiuqian Mu, William H. Klein, Nadean L Brown, Jeffrey T. Wigle, Carol Schuurmans, David D. Eisenstat

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/ Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 doubleknockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo. We suggest that ATOH7 specifies RGC-committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate.

Original languageEnglish (US)
Pages (from-to)1698-1711
Number of pages14
JournalDevelopment (Cambridge)
Volume144
Issue number9
DOIs
StatePublished - May 1 2017

Fingerprint

Retinal Ganglion Cells
Vertebrates
Retina
Cell Differentiation
Basic Helix-Loop-Helix Transcription Factors
Amacrine Cells
Homeobox Genes
Knockout Mice
Ganglia
Maintenance
Phenotype

Keywords

  • Atoh7
  • Chromatin immunoprecipitation
  • Homeobox
  • In utero electroporation
  • Math5
  • Mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Zhang, Q., Zagozewski, J., Cheng, S., Dixit, R., Zhang, S., de Melo, J., ... Eisenstat, D. D. (2017). Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. Development (Cambridge), 144(9), 1698-1711. https://doi.org/10.1242/dev.142042

Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. / Zhang, Qi; Zagozewski, Jamie; Cheng, Shaohong; Dixit, Rajiv; Zhang, Shunzhen; de Melo, Jimmy; Mu, Xiuqian; Klein, William H.; Brown, Nadean L; Wigle, Jeffrey T.; Schuurmans, Carol; Eisenstat, David D.

In: Development (Cambridge), Vol. 144, No. 9, 01.05.2017, p. 1698-1711.

Research output: Contribution to journalArticle

Zhang, Q, Zagozewski, J, Cheng, S, Dixit, R, Zhang, S, de Melo, J, Mu, X, Klein, WH, Brown, NL, Wigle, JT, Schuurmans, C & Eisenstat, DD 2017, 'Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina', Development (Cambridge), vol. 144, no. 9, pp. 1698-1711. https://doi.org/10.1242/dev.142042
Zhang, Qi ; Zagozewski, Jamie ; Cheng, Shaohong ; Dixit, Rajiv ; Zhang, Shunzhen ; de Melo, Jimmy ; Mu, Xiuqian ; Klein, William H. ; Brown, Nadean L ; Wigle, Jeffrey T. ; Schuurmans, Carol ; Eisenstat, David D. / Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. In: Development (Cambridge). 2017 ; Vol. 144, No. 9. pp. 1698-1711.
@article{b4fd5c1c328245d6932a0e8e203e0c82,
title = "Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina",
abstract = "Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/ Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 doubleknockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo. We suggest that ATOH7 specifies RGC-committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate.",
keywords = "Atoh7, Chromatin immunoprecipitation, Homeobox, In utero electroporation, Math5, Mouse",
author = "Qi Zhang and Jamie Zagozewski and Shaohong Cheng and Rajiv Dixit and Shunzhen Zhang and {de Melo}, Jimmy and Xiuqian Mu and Klein, {William H.} and Brown, {Nadean L} and Wigle, {Jeffrey T.} and Carol Schuurmans and Eisenstat, {David D.}",
year = "2017",
month = "5",
day = "1",
doi = "10.1242/dev.142042",
language = "English (US)",
volume = "144",
pages = "1698--1711",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "9",

}

TY - JOUR

T1 - Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina

AU - Zhang, Qi

AU - Zagozewski, Jamie

AU - Cheng, Shaohong

AU - Dixit, Rajiv

AU - Zhang, Shunzhen

AU - de Melo, Jimmy

AU - Mu, Xiuqian

AU - Klein, William H.

AU - Brown, Nadean L

AU - Wigle, Jeffrey T.

AU - Schuurmans, Carol

AU - Eisenstat, David D.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/ Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 doubleknockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo. We suggest that ATOH7 specifies RGC-committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate.

AB - Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/ Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 doubleknockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo. We suggest that ATOH7 specifies RGC-committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate.

KW - Atoh7

KW - Chromatin immunoprecipitation

KW - Homeobox

KW - In utero electroporation

KW - Math5

KW - Mouse

UR - http://www.scopus.com/inward/record.url?scp=85018780796&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018780796&partnerID=8YFLogxK

U2 - 10.1242/dev.142042

DO - 10.1242/dev.142042

M3 - Article

C2 - 28356311

AN - SCOPUS:85018780796

VL - 144

SP - 1698

EP - 1711

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 9

ER -