BMP-2 decreases Mash1 stability by increasing Id1 expression

Abstract

In neural development, bone morphogenetic proteins (BMPs) restrict neuronal differentiation, thereby promoting the maintenance of progenitor cells or even inducing astrocytogenesis. We report that exposure of neuroendocrine lung carcinoma cells to BMP-2 leads to a rapid decline in steady-state levels of Mash1 protein and some neuron-specific markers. BMP-2 induces a post-transcriptional decrease in Mash1 levels through enhanced degradation. We demonstrate that Mash1 protein stability is tightly regulated by the E47/Id1 expression ratio. Transient induction of Id1 by BMP-2 negatively correlates with Mash1 levels. Furthermore, an ectopic increase in Id1 levels is sufficient to induce degradation of either ectopic or endogenous Mash1, whereas expression of Mash1 in Id1-deficient cells or overexpression of E47 makes Mash1 levels refractory to the addition of BMP-2. Furthermore, we show that the E47/Id1 expression ratio also regulates CK2-mediated phosphorylation of Mash1 on Ser152, which increases interaction of Mash1-E47 heterodimers. We propose a novel mechanism in which the balance between Id and E protein levels regulates not only the transcriptional function but also protein stability of the neurogenic bHLH transcription factor Mash1.

Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1

“…As development proceeds, this signal may also act in migrating GABAergic interneurons since PI3K has been reported to regulate tangential migration of neocortical interneurons (44). Proneural bHLH proteins are key determinants of neuronal fate in the developing telencephalon (13,15), and several studies have shown how these proteins are regulated posttranscriptionally by extrinsic cues (20)(21)(22)(23)(24). Our data now suggest that the PDK1-Akt pathway mediates regulation of Mash1 by extrinsic cues.…”

“…Ngns and Mash1 are expressed in complementary patterns in the dorsal and ventral parts of the telencephalon, contributing to the generation of glutamatergic and GABAergic neurons, respectively (17,18). Although some transcriptional/posttranscriptional regulations on these transcription factors have been revealed, it largely remains unclear how they are regulated by neurogenic extrinsic cues during CNS development (7,(19)(20)(21)(22)(23)(24).…”

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

“…Surprisingly, Smads, the main transcriptional effectors of BMPs, do not seem to play a major role in regulating gene expression in BMP-treated quiescent NS cells, since the consensus Smad-binding motif is not significantly overrepresented in enhancers active in quiescent NS cells (data not shown). Genes of the inhibitor of differentiation (Id) family are major targets of BMP signaling in many tissues, including the embryonic nervous system (Nakashima et al 2001;Samanta and Kessler 2004;Vinals et al 2004). The four family members, and particularly Id1 and Id4, are highly up-regulated in quiescent NS cells and may therefore contribute significantly to the quiescence-inducing activity of BMP.…”

Inhibitors of Differentiation and DNA Binding (Ids) Regulate Math1 and Hair Cell Formation during the Development of the Organ of Corti

“…Vinals et al (2004) demonstrated that overexpression of E47 can sequester Id proteins, thus inhibiting Id function. However, overexpression of E47 did not have any obvious influence on progenitor cell fates.…”