title: Regulation ofBrn3bby 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 thatDlx1,Dlx2andBrn3bhomeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generatedDlx1/Dlx2/Brn3btriple-knockout mice. A more severe retinal phenotype was found in theDlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of theBrn3bsingle- andDlx1/Dlx2double-knockout 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 ofBrn3bexpression. Knockdown ofDlx2expression in primary embryonic retinal cultures andDlx2gain of functionin uterostrongly support that DLX2 is both necessary and sufficient forBrn3bexpressionin vivoWe suggest that ATOH7 specifies RGC-committed progenitors and thatDlx1andDlx2function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation ofBrn3bexpression to determine RGC fate.
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada R3E 0J9.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Canada T6G 2H7.
authors.forename: Jamie
authors.initials: J
authors.lastname: Zagozewski
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada R3A 1S1.
authors.forename: Shaohong
authors.identifier: 0000-0003-2130-9050
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Canada T2N 4N1.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Dixit
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada R3E 3J7.
authors.forename: Shunzhen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada R3E 0J9.
authors.forename: Jimmy
authors.initials: J
authors.lastname: de Melo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiuqian
authors.initials: X
authors.lastname: Mu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Klein
authors.affiliation: Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, Canada.
authors.forename: Nadean L
authors.initials: NL
authors.lastname: Brown
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada R3E 3J7.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Wigle
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Canada T2N 4N1.
authors.forename: Carol
authors.initials: C
authors.lastname: Schuurmans
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada R3E 0J9 eisensta@ualberta.ca.|Department of Medical Genetics, University of Alberta, Edmonton, Canada T6G 2H7.|Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada R3A 1S1.|Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada R3E 3J7.|Department of Ophthalmology, University of Manitoba, Winnipeg, Canada R3T 2N2.
authors.forename: David D
authors.identifier: 0000-0002-5976-0798
authors.initials: DD
authors.lastname: Eisenstat
mesh_terms: D025042:Amacrine Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D059329:Cholinergic Neurons / Q000166:cytology / Q000378:metabolism; D018274:Electroporation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000378:metabolism*; D050820:Transcription Factor Brn-3B / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D014714:Vertebrates / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; C117638:Atoh7 protein, mouse; C088334:Distal-less homeobox proteins; C085559:Pou4f2 protein, mouse
keywords: Atoh7; Chromatin immunoprecipitation; Homeobox; In utero electroporation; Math5; Mouse