Insulinoma-Associated 1 Has a Panneurogenic Role and Promotes the Generation and Expansion of Basal Progenitors in the Developing Mouse Neocortex

Abstract

Basal (intermediate) progenitors are the major source of neurons in the mammalian neocortex. The molecular machinery governing basal progenitor biogenesis is unknown. Here, we show that the zinc-finger transcription factor Insm1 (insulinoma-associated 1) is expressed specifically in progenitors undergoing neurogenic divisions, has a panneurogenic role throughout the brain, and promotes basal progenitor formation in the neocortex. Mouse embryos lacking Insm1 contained half the number of basal progenitors and showed a marked reduction in cortical plate radial thickness. Forced premature expression of Insm1 in neuroepithelial cells resulted in their mitosis occurring at the basal (rather than apical) side of the ventricular zone and induced expression of the basal progenitor marker Tbr2. Remarkably, these cells remained negative for Tis21, a marker of neurogenic progenitors, and did not generate neurons but underwent self-amplification. Our data imply that Insm1 is involved in the generation and expansion of basal progenitors, a hallmark of neocortex evolution.

The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

“…Furthermore, genes known to perform opposing actions to Hes1 by promoting the expression of proneural genes, including Pax6 and Btg2, were up-regulated (5,28). Other upregulated transcription factors with proneuronal functions included Insm1, Myt1l, and Brn2 (29,30). Consistent with these findings, molecular markers for intermediate progenitor (Eomes), immature (Dcx), and mature (Mapt, Nefh, and Rbfox3) neurons also were upregulated in Dmrta2 −/− cells (Fig.…”

Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest

“…INSM1 mutant mice also show a marked change in the terminal differentiation of chromaffin cells and reduced expression of genes whose protein products control catecholamine synthesis and secretion (6). INSM1 has a pan-neurogenic role and promotes the generation and expansion of basal progenitors in the developing mouse neocortex (22). Furthermore, the homolog Ol-insm1b is strongly expressed in a Medaka model during neurogenesis and pancreas organogenesis, where it plays a role in cell cycle exit and down-regulates cell proliferation during development without triggering apoptosis (23).…”

A Prominent Couple

“…The most commonly expressed AR splice variant is AR-V7, resulting from splicing of exon 3 to a cryptic exon in the intron between exon 3 and 4 generating a truncated AR protein lacking the ligand-binding domain, but retaining transcriptional activity [60,61]. AR-V7 could be detected in primary untreated PCa at low levels, but showed an increased ratio relative to full length AR in metastatic CRPC (mCRPC) [24,62]. AR-V7 has been implicated in abiraterone and enzalutamide resistance and correlated to disease progression and mortality [24,62,63].…”

“…AR-V7 could be detected in primary untreated PCa at low levels, but showed an increased ratio relative to full length AR in metastatic CRPC (mCRPC) [24,62]. AR-V7 has been implicated in abiraterone and enzalutamide resistance and correlated to disease progression and mortality [24,62,63]. In VCaP cells, androgen deprivation using enzalutamide induced expression of AR-V7 [64].…”

“…The SNP profiles matched known profiles or were unique. The purity of cell lines was validated using the Multiplex cell Contamination Test by Multiplexion (Heidelberg, Germany) as described recently [62]. No Mycoplasma, SMRV or interspecies contamination was detected.…”