Zbtb20 modulates the sequential generation of neuronal layers in developing cortex

Abstract

BackgroundDuring corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown.ResultsHere, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities. Zbtb20 knock out mice exhibited enhanced populations of early born L6-L4 neuronal subtypes and a dramatic reduction of the late born L3/L2 neurons. This defect was due to a temporal misbalance in the production of earlier versus later born neurons, leading to a progressive diminishing of the progenitor pool for the generation of L3-L2 neurons. Zbtb20 implements these temporal effects in part by binding to promoter of the orphan nuclear receptor CoupTF1/Nr2f1. In addition to its effects exerted in cortical progenitors, the postmitotic expression of Zbtb20 in L3/L2 neurons starting at birth may contribute to their proper differentiation and migration.ConclusionsOur findings reveal Zbtb20 as a novel temporal regulator for the generation of layer-specific neuronal identities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0242-2) contains supplementary material, which is available to authorized users.

Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies

“…In the hippocampus, Zbtb20 has been shown to act as a direct repressor of genes that control projection neurons development in the neocortex (Nielsen, Thomassen, Møllgård, Noraberg, & Jensen, ), suggesting that dysfunction of ZBTB20 in patients leads to abnormal repression of these target genes with subsequent misspecification of the hippocampal formation observed in Case 1. In addition to the hippocampus, Zbtb20 expression pattern was recently extended to the neocortex especially within upper‐layer cortical neurons (Tonchev et al, ). As a consequence, Zbtb20 deficiency in mice results in abnormal cortical neuronal identities as revealed by an increased in lower layer neuronal subtypes and a reduction of upper‐layer neurons that make most callosal projections.…”

“…As a consequence, Zbtb20 deficiency in mice results in abnormal cortical neuronal identities as revealed by an increased in lower layer neuronal subtypes and a reduction of upper‐layer neurons that make most callosal projections. Among Zbtb20 targets are genes required for the specification of callosal projection neurons such as Satb2 (Alcamo et al, ), Brn2 (Nagao et al, ), Coup‐TF1/Nr2f1 (Tonchev et al, ), as well as Cux1 and Cux2 (Zimmer, Tiveron, Bodmer, & Cremer, ). In addition, Zbtb20 directly regulates Mef2 c which in humans is mutated or deleted in mental retardation syndrome‐20 (MRD20; MIM613443), a disorder frequently associated with CCAs (Le Meur et al, ; Novara et al, ).…”

“…ZBTB20 encodes a transcriptional repressor of the broad complex tram track brick‐a‐brack (BTB) zinc finger family composed of an N‐terminal BTB domain involved in protein–protein interaction and five C2H2 Krüppel‐type zinc finger domains conferring DNA‐binding ability. In mice, Zbtb20 has been proposed to act as a transcriptional repressor essential for cell fate determination throughout both hippocampal and neocortical development (Nagao, Ogata, Sawada, & Gotoh, ; Rosenthal, Tonchev, Stoykova, & Chowdhury, ; Tonchev, Tuoc, Rosenthal, Studer, & Stoykova, ; Xie et al, ).…”

A single cell transcriptome atlas of the developing zebrafish hindbrain

“…In the next group, a subset of genes initiates expression that then increases late in pseudotime (G5). They include zbtb20, which functions during corticogenesis as a temporal regulator for the generation of layerspecific neuronal subtypes (Tonchev et al, 2016), and the less studied uncx, nhlh2, lhx4 and sox12. Furthermore, members of the zebrafish scratch family (scrt1a/scrt1b/scrt2) have a similar dynamic pattern and show enrichment within the neurogenic zone, with some dorsoventral differences: scrt1a and scrt1b are expressed ventrally and dorsally (Fig.…”

A single cell transcriptome atlas of the developing zebrafish hindbrain

“…In the next group, a subset of genes initiates expression that then declines late in pseudotime (G5a). They include zbtb20 that functions during corticogenesis as in the generation of layer-specific neuronal subtypes (Tonchev et al, 2016), and the less-studied uncx, nhlh2, lhx4 and sox12. Furthermore, members of the scratch family (scrt1a/b/2) has a similar dynamic pattern, with enrichment within the neurogenic zone and some dorso-ventral differences: scrt1a and scrt1b are expressed ventral and dorsal (Fig.…”