title: Sip1 regulates the generation of the inner nuclear layer retinal cell lineages in mammals.
abstract: The transcription factor Sip1 (Zeb2) plays multiple roles during CNS development from early acquisition of neural fate to cortical neurogenesis and gliogenesis. In humans, SIP1 (ZEB2) haploinsufficiency leads to Mowat-Wilson syndrome, a complex congenital anomaly including intellectual disability, epilepsy and Hirschsprung disease. Here we uncover the role of Sip1 in retinogenesis. Somatic deletion of Sip1 from mouse retinal progenitors primarily affects the generation of inner nuclear layer cell types, resulting in complete loss of horizontal cells and reduced numbers of amacrine and bipolar cells, while the number of Muller glia is increased. Molecular analysis places Sip1 downstream of the eye field transcription factor Pax6 and upstream of Ptf1a in the gene network required for generating the horizontal and amacrine lineages. Intriguingly, characterization of differentiation dynamics reveals that Sip1 has a role in promoting the timely differentiation of retinal interneurons, assuring generation of the proper number of the diverse neuronal and glial cell subtypes that constitute the functional retina in mammals.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Menuchin-Lasowski
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
authors.forename: Pazit
authors.initials: P
authors.lastname: Oren-Giladi
authors.affiliation: Department of Ophthalmology & Visual Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot 7610001, Israel.
authors.forename: Raaya
authors.initials: R
authors.lastname: Ezra-Elia
authors.affiliation: Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot 7610001, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Ofri
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
authors.forename: Shany
authors.initials: S
authors.lastname: Peled-Hajaj
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Farhy
authors.affiliation: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven 3000, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van de Putte
authors.affiliation: Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo Motoyama, Kita-ku, Kyoto 603-8555, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kondoh
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven 3000, Belgium Department of Cell Biology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: Department of Ophthalmology & Visual Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel ruthash@post.tau.ac.il.
authors.forename: Ruth
authors.identifier: 0000-0002-5364-6898
authors.initials: R
authors.lastname: Ashery-Padan
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D005260:Female; D005455:Fluorescent Antibody Technique; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D000071841:PAX6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012160:Retina / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; C000605732:Pax6 protein, mouse; C491561:Sip1 protein, mouse; D014157:Transcription Factors; C062602:transcription factor PTF1
keywords: Differentiation; Neurogenesis; Progenitor; Retina; Retinogenesis; Sip1; Zeb2; Zfhx1b