A Casz1–NuRD complex regulates temporal identity transitions in neural progenitors

Abstract

Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in the correct sequence and proportions. A number of temporal identity factors that control these transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal development. We show that Casz1 is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As additional temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through this common biochemical process to regulate neurogenesis.

Chromatin Remodeling in the Brain-a NuRDevelopmental Odyssey

“…Suppression of gliogenesis was also phenocopied by Polycomb loss-of-function. Although we did not formally demonstrate that NuRD controls Polycomb recruitment, Polycomb proteins were observed to associate with Casz1 [ 33 , 34 ], suggesting a physical linkage between these protein complexes. We propose that Casz1 suppresses gliogenesis by recruiting the NuRD complex to target genes, leading to histone deacetylation and Polycomb occupancy.…”

“…Moreover, there is an intimate linkage between NuRD and Polycomb repressor complexes (PRCs) at subsets of genomic locations [ 28 , 32 ]. Accordingly, biochemical and functional interactions between these complexes have been repeatedly observed in neural cells (see below) [ 33 , 34 , 35 , 36 ].…”

“…We previously showed that murine Casz1 is dynamically expressed during retinal development and alters the output of retinal progenitors [ 107 ]. To understand how Casz1 functions mechanistically, we and others performed proteomics and found that Casz1 interacts with the NuRD complex [ 34 , 108 ]. In multipotent retinal progenitors, the interaction between Casz1 and NuRD regulated the production of neurons versus glia.…”

“…In multipotent retinal progenitors, the interaction between Casz1 and NuRD regulated the production of neurons versus glia. When either Casz1 or the NuRD complex was abrogated, the production of earlier-born rod photoreceptors was decreased, while later-born Müller glia were concomitantly increased [ 34 ]. This effect required HDAC activity and was phenocopied by overexpressing a fragment of GATAD2A that functions as a dominant negative to block the association of Chd4 protein with NuRD [ 72 ].…”

“…( C ) Chd4 RNAi has also been linked to premature gliogenesis in neocortical cells, although this effect may be independent of NuRD [ 35 ]. ( D ) Casz1 conditional mutant retinal progenitors overproduce glia at the expense of rod photoreceptors in a NuRD-dependent fashion [ 34 ]. ( E ) In neocortical cells, Chd3/5 RNAi disrupts neuronal migration at distinct phases [ 13 ].…”