BMP signaling in telencephalic neural cell specification and maturation

Abstract

Bone morphogenetic proteins (BMPs) make up a family of morphogens that are critical for patterning, development, and function of the central and peripheral nervous system. Their effects on neural cells are pleiotropic and highly dynamic depending on the stage of development and the local niche. Neural cells display a broad expression profile of BMP ligands, receptors, and transducer molecules. Moreover, interactions of BMP signaling with other incoming morphogens and signaling pathways are crucial for most of these processes. The key role of BMP signaling suggests that it includes many regulatory mechanisms that restrict BMP activity both temporally and spatially. BMPs affect neural cell fate specification in a dynamic fashion. Initially they inhibit proliferation of neural precursors and promote the first steps in neuronal differentiation. Later on, BMP signaling effects switch from neuronal induction to promotion of astroglial identity and inhibition of neuronal or oligodendroglial lineage commitment. Furthermore, in postmitotic cells, BMPs regulate cell survival and death, to modulate neuronal subtype specification, promote dendritic and axonal growth and induce synapse formation and stabilization. In this review, we examine the canonical and non-canonical mechanisms of BMP signal transduction. Moreover, we focus on the specific role of BMPs in the nervous system including their ability to regulate neural stem cell proliferation, self-renewal, lineage specification, and neuronal function.

Keywords: BMP; morphogen; neural development; neural differentiation; signal transduction; synaptogenesis.

FIGURE 1

Canonical BMP signaling. BMPs bind to the BMP receptors type I and II, and then type II receptor phosphorylates and activates the type I BMP receptor. Activated type I receptor phosphorylates R-Smads, which associate with the common Smad (Smad4) and enter the nucleus, where they regulate transcriptional processes. BMP signaling can be inhibited by extracellular antagonists, such as Noggin and Chordin, or intracellularly by I-Smads.

FIGURE 2

Non-canonical BMP signaling. In addition to Smads, activated BMP receptors activate several intracellular pathways which modulate BMP-dependent cellular responses. Pathways include TAK-p38, PI3-kinase, Cdc42 or activation of LIMK by binding to the BMPR-II cytoplasmic tail.

FIGURE 3

Roles of BMP signaling in neural development. Initially, inhibition of BMP signaling is required for neuroectoderm induction. BMPs generate a signaling gradient and promote dorsomedial identity. BMP signaling is prominent at the dorsal telencephalic midline and in the marginal zone neurons, where it correlates negatively with expression of the cortical selector Lhx2, Fgf8, or Shh. In late embryogenesis and postnatally, BMP signaling promotes astroglial commitment by activation astrocyte-specific promoters through a Stat3-p300/CBP-Smad1 complex. At the same time represses commitment to the other two neural lineages by inducing Ids and Hes proteins. In adulthood, a balanced BMP signaling is required for regulation of quiescence and differentiation of neural stem cell populations in the SVZ and SGZ.

FIGURE 4

Model of mechanism of repression of neurogenic bHLH transcription factors by BMPs. (A) In differentiating neurogenic precursors, bHLH transcription factors hetero-dimerizes with E proteins, which bind to E boxes and promote expression of neuronal genes. (B) Activation of the BMP signaling pathway leads to increased levels of Id and Hes proteins. Id and Hes proteins sequester E proteins away from bHLH transcription factors, which leads to transcriptionally inactive complexes and also enhance degradation of bHLH monomers. Furthermore Hes proteins can bind to N boxes sequences in neural promoters and recruit the Groucho family of transcriptional repressors.

FIGURE 5

Retrograde signaling of BMPs in synapse formation. BMP retrograde transport of endocytosed BMP receptors by dynein motors. Effective retrograde BMP signal also involves specific translation of Smad protein in the axons.