title: Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis.
abstract: Retinogenesis is a precisely controlled developmental process during which different types of neurons and glial cells are generated under the influence of intrinsic and extrinsic factors. Three transcription factors, Foxn4, RORβ1 and their downstream effector Ptf1a, have been shown to be indispensable intrinsic regulators for the differentiation of amacrine and horizontal cells. At present, however, it is unclear how Ptf1a specifies these two cell fates from competent retinal precursors. Here, through combined bioinformatic, molecular and genetic approaches in mouse retinas, we identify the Tfap2a and Tfap2b transcription factors as two major downstream effectors of Ptf1a. RNA-seq and immunolabeling analyses show that the expression of Tfap2a and 2b transcripts and proteins is dramatically downregulated in the Ptf1a null mutant retina. Their overexpression is capable of promoting the differentiation of glycinergic and GABAergic amacrine cells at the expense of photoreceptors much as misexpressed Ptf1a is, whereas their simultaneous knockdown has the opposite effect. Given the demonstrated requirement for Tfap2a and 2b in horizontal cell differentiation, our study thus defines a Foxn4/RORβ1-Ptf1a-Tfap2a/2b transcriptional regulatory cascade that underlies the competence, specification and differentiation of amacrine and horizontal cells during retinal development.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, China. kxjin@yahoo.com.
authors.forename: Kangxin
authors.initials: K
authors.lastname: Jin
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Rutgers University-Robert Wood Johnson Medical School, 679 Hoes Lane West, Piscataway, NJ, 08854, USA. hjiang14@jhmi.edu.|Present address: Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21206, USA. hjiang14@jhmi.edu.
authors.forename: Haisong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, China. xdc1115@163.com.
authors.forename: Dongchang
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Rutgers University-Robert Wood Johnson Medical School, 679 Hoes Lane West, Piscataway, NJ, 08854, USA. mz2484@columbia.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Zou
authors.affiliation: Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. jun.zhu@nih.gov.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, China. xiang@cabm.rutgers.edu.|Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Rutgers University-Robert Wood Johnson Medical School, 679 Hoes Lane West, Piscataway, NJ, 08854, USA. xiang@cabm.rutgers.edu.
authors.forename: Mengqing
authors.initials: M
authors.lastname: Xiang
mesh_terms: D025042:Amacrine Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D005136:Eye Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D055495:Neurogenesis; D012160:Retina / Q000166:cytology*; D051248:Retinal Horizontal Cells / Q000166:cytology / Q000378:metabolism; D017423:Sequence Analysis, RNA; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D051858:Forkhead Transcription Factors; C438622:Foxn4 protein, mouse; C493668:Tfap2a protein, mouse; C493669:Tfap2b protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C062602:transcription factor PTF1