The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation

Abstract

The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal-ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways.

Figure 1

Canonical BMP signaling. BMP signaling is transduced by a series of phosphorylation events. When BMP ligands bind their receptors, BMP Type II receptors transphosphorylate Type I receptors, which in turn phosphorylate R-Smads. Activated R-Smads bind with Co-Smads and translocate into the nucleus. In the nucleus, the R-Smad-Co-Smad complexes interact with transcription factors (TF) and other coregulatory proteins to control gene expression. BMP signaling can be inhibited extracellularly by antagonists, such as Noggin, which competitively bind BMP ligands. Intracellulary, inhibitory Smads (I-Smads) bind to activated R-Smads and prevent their binding with Co-Smads. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

BMP signaling during neurulation. A: A gradient of BMP signaling is established in ectoderm by BMP inhibitors. Neural plate formation is induced where BMP signaling is absent. B: The neural plate folds to create the neural groove and finally pinches off from the overlying ectoderm, forming the neural tube. C: The ectoderm and neural tube roof plate (RP) continue to secrete BMP ligands, which directly oppose ventrally secreted Shh from the notochord and floor plate (FP). The dual morphogen gradient of BMP and Shh establishes the dorsal–ventral axis and specifies neuron populations along this axis. Intermediate levels of BMPs induce neural crest cells. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

BMP signaling in adult neurogenic niches. Adult brains contain two neurogenic niches, the SVZ and the SGZ. A: In the SVZ, radial glial-like (RGL) stem cells divide to give rise to transient amplifying cells (TAP) which rapidly divide to become neuroblasts (NB). These immature neurons travel through the rostral migratory stream to the olfactory bulb where they become interneurons. RGL stem cells and TAPs secrete BMP ligands, whereas ependymal cells secrete Noggin. BMP signaling in the SVZ promotes astroglial lineage commitment and promotes survival of neuronally committed neuroblasts. B: In the hippocampal SGZ of the dentate gyrus, RGL stem cells divide to give rise to TAPs, which in turn produce NBs, similar to the SVZ. NBs migrate radially into the granule cell layer (GCL) where they become mature dentate granule cells. Unlike in the SVZ, the sources of BMP ligands and Noggin have not yet been clearly identified in the SGZ. While noggin is required to maintain the proliferating, self-renewing population of stem cells, BMP signaling seems to block neurogenesis, indicating that a balance of BMP signaling regulates neurogenesis in the SGZ niche. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

The changing roles of BMP signaling. BMP signaling is involved in numerous aspects of neural stem cell development. Initially, inhibition of BMP signaling is required for neuroectoderm induction. A gradient of BMP signaling establishes the dorsal–ventral axis and specifies neural crest cells and distinct interneuron subgroups within the spinal cord. During forebrain development, BMP signaling promotes neuronal lineage commitment while inhibiting oligodendrocyte formation. In late embryogenesis and postnatally, BMP signaling changes to promote astroglial commitment while repressing commitment to the other two neural lineages. In adulthood, a balance of BMP signaling is critical for maintenance and differentiation of neural stem cell populations in the SVZ and SGZ. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]