title: Hedgehog-dependent E3-ligase Midline1 regulates ubiquitin-mediated proteasomal degradation of Pax6 during visual system development.
abstract: Pax6 is a key transcription factor involved in eye, brain, and pancreas development. Although pax6 is expressed in the whole prospective retinal field, subsequently its expression becomes restricted to the optic cup by reciprocal transcriptional repression of pax6 and pax2 However, it remains unclear how Pax6 protein is removed from the eyestalk territory on time. Here, we report that Mid1, a member of the RBCC/TRIM E3 ligase family, which was first identified in patients with the X-chromosome-linked Opitz BBB/G (OS) syndrome, interacts with Pax6. We found that the forming eyestalk is a major domain of mid1 expression, controlled by the morphogen Sonic hedgehog (Shh). Here, Mid1 regulates the ubiquitination and proteasomal degradation of Pax6 protein. Accordantly, when Mid1 levels are knocked down, Pax6 expression is expanded and eyes are enlarged. Our findings indicate that remaining or misaddressed Pax6 protein is cleared from the eyestalk region to properly set the border between the eyestalk territory and the retina via Mid1. Thus, we identified a posttranslational mechanism, regulated by Sonic hedgehog, which is important to suppress Pax6 activity and thus breaks pax6 autoregulation at defined steps during the formation of the visual system.
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pfirrmann
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany;
authors.forename: Enrico
authors.initials: E
authors.lastname: Jandt
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany; Gynecological Hospital, University Medical Center Mannheim, 68167 Mannheim, Germany;
authors.forename: Swantje
authors.initials: S
authors.lastname: Ranft
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany;
authors.forename: Ashwin
authors.initials: A
authors.lastname: Lokapally
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany;
authors.forename: Herbert
authors.initials: H
authors.lastname: Neuhaus
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Univ Paris Sud, Université Paris-Saclay, 91405 Orsay, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Institute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany; thomas.hollemann@medizin.uni-halle.de.
authors.forename: Thomas
authors.identifier: 0000-0002-5168-4540
authors.initials: T
authors.lastname: Hollemann
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian; D005123:Eye / Q000254:growth & development / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006367:HeLa Cells; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009929:Organ Size; D038081:Organogenesis / Q000235:genetics; D000071841:PAX6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D053823:Hedgehog Proteins; D000071841:PAX6 Transcription Factor; C000605731:Pax6 protein, Xenopus; C558166:Shh protein, Xenopus; D029867:Xenopus Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: Xenopus; eye development; mid1; pax6; ubiquitin