Sip1 regulates the generation of the inner nuclear layer retinal cell lineages in mammals

Development. 2016 Aug 1;143(15):2829-41. doi: 10.1242/dev.136101. Epub 2016 Jul 6.

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.

Keywords: Differentiation; Neurogenesis; Progenitor; Retina; Retinogenesis; Sip1; Zeb2; Zfhx1b.

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Lineage
  • Chromatin Immunoprecipitation
  • Female
  • Fluorescent Antibody Technique
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis / genetics
  • Neurogenesis / physiology
  • PAX6 Transcription Factor / genetics
  • PAX6 Transcription Factor / metabolism
  • Pregnancy
  • Retina / cytology*
  • Retina / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Nerve Tissue Proteins
  • PAX6 Transcription Factor
  • Pax6 protein, mouse
  • Sip1 protein, mouse
  • Transcription Factors
  • transcription factor PTF1