Zeb2 regulates the balance between retinal interneurons and Müller glia by inhibition of BMP-Smad signaling.

Developmental biology 2020 Dec 01

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The interplay between signaling molecules and transcription factors during retinal development is key to controlling the correct number of retinal cell types. Zeb2 (Sip1) is a zinc-finger multidomain transcription factor that plays multiple roles in central and peripheral nervous system development. Haploinsufficiency of ZEB2 causes Mowat-Wilson syndrome, a congenital disease characterized by intellectual disability, epilepsy and Hirschsprung disease. In the developing retina, Zeb2 is required for generation of horizontal cells and the correct number of interneurons; however, its potential function in controlling gliogenic versus neurogenic decisions remains unresolved. Here we present cellular and molecular evidence of the inhibition of Müller glia cell fate by Zeb2 in late stages of retinogenesis. Unbiased transcriptomic profiling of control and Zeb2-deficient early-postnatal retina revealed that Zeb2 functions in inhibiting Id1/2/4 and Hes1 gene expression. These neural progenitor factors normally inhi bit neural differentiation and promote Müller glia cell fate. Chromatin immunoprecipitation (ChIP) supported direct regulation of Id1 by Zeb2 in the postnatal retina. Reporter assays and ChIP analyses in differentiating neural progenitors provided further evidence that Zeb2 inhibits Id1 through inhibition of Smad-mediated activation of Id1 transcription. Together, the results suggest that Zeb2 promotes the timely differentiation of retinal interneurons at least in part by repressing BMP-Smad/Notch target genes that inhibit neurogenesis. These findings show that Zeb2 integrates extrinsic cues to regulate the balance between neuronal and glial cell types in the developing murine retina. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Yotam Menuchin-Lasowski, Bar Dagan, Andrea Conidi, Mazal Cohen-Gulkar, Ahuvit David, Marcelo Ehrlich, Pazit Oren Giladi, Brian S Clark, Seth Blackshaw, Keren Shapira, Danny Huylebroeck, Yoav I Henis, Ruth Ashery-Padan. Zeb2 regulates the balance between retinal interneurons and Müller glia by inhibition of BMP-Smad signaling. Developmental biology. 2020 Dec 01;468(1-2):80-92