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Review
. 2016;2016:9260592.
doi: 10.1155/2016/9260592. Epub 2016 May 16.

Bone Morphogenetic Protein 4 Signalling in Neural Stem and Progenitor Cells During Development and After Injury

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Free PMC article
Review

Bone Morphogenetic Protein 4 Signalling in Neural Stem and Progenitor Cells During Development and After Injury

Alistair E Cole et al. Stem Cells Int. .
Free PMC article

Abstract

Substantial progress has been made in identifying the extracellular signalling pathways that regulate neural stem and precursor cell biology in the central nervous system (CNS). The bone morphogenetic proteins (BMPs), in particular BMP4, are key players regulating neuronal and glial cell development from neural precursor cells in the embryonic, postnatal, and injured CNS. Here we review recent studies on BMP4 signalling in the generation of neurons, astrocytes, and oligodendroglial cells in the CNS. We also discuss putative mechanisms that BMP4 may utilise to influence glial cell development following CNS injury and highlight some questions for further research.

Figures

Figure 1
Figure 1
General BMP4 cellular signalling pathway. BMP4 dimers may bind to preformed complexes (PFCs, A), in which BMPRI Type I and Type II receptors are already bound at the cell surface, or by firstly binding to the Type I receptor and inducing the Type II receptor to the complex (BMP-induced signalling complex or BISC, B). Repulsive guidance molecules (RGMa, DRAGON, etc.) may enhance binding of the BMP4 dimer to the Type I receptors in both PFC and BISC binding (C). In the canonical SMAD-dependent pathway, the constitutively active Type II receptor kinase domain phosphorylates a glycine-serine-rich area known as the “GS box” on the Type I receptor (D). The activated Type I receptor sequentially phosphorylates receptor-associated SMADs (SMAD1, SMAD5, and SMAD8 in the case of BMP4) (E). These receptor-associated SMADs then form complexes with Co-SMAD4 (F), enter the nucleus, and further associate with cobinding partners including p300, CBP, STATs, and others (G). These heteromeric complexes then act as transcription factors to regulate the expression of neuronal and glial gene products (H). Extracellular inhibitors of the BMP4, such as noggin, bind BMP4 prior to receptor binding (I). Pseudoreceptors such as BAMBI bind BMP4 dimers but do not propagate downstream signalling activity to a lack of an intracellular kinase domain (J). Other inhibitory intracellular factors include SMAD6, SMAD7, and SMURF. SMAD6 competes with SMAD4 for binding to receptor-associated SMADs (K), SMAD7 blocks the kinase domain of BMP Type I receptors (L), and SMURF mediates ubiquitination and subsequent proteasomal degradation of receptor SMAD1, SMAD5, and SMAD8 (M). Other SMAD-independent pathways may be activated by BMP4, such as MAPK/p38, JNK, Erk, and PI3K (MAPK/p38 pathway shown in this figure).
Figure 2
Figure 2
RNA-Seq transcriptome analysis showing increased transcription of Bmp4 transcripts in OPCs and newly formed oligodendrocytes in postnatal mice compared to other CNS cells. This is unique to Bmp4; closely related BMP2 does not show similar levels of increased transcription in oligodendroglial lineage cells compared to other CNS cells. Additionally, increased Bmp4 transcription does not appear to be counteracted by concomitant transcriptional increases expression of BMP inhibitors, such as noggin and chordin. The functional relevance of increased Bmp4 transcription by OPCs and immature oligodendrocytes remains to be clarified (FPKM = fragments per kilobase of transcript per million mapped reads.).
Figure 3
Figure 3
Simplified diagram of adult SVZ illustrating BMP4 involvement in NSC development. Adult NSCs (B cells) are specified from radial glia-like cells during prenatal development. Neuroblasts (A cells) and transient amplifying progenitors (B cells) are derived from NSCs and generate neurons and glia. Ependymal cells provide support by regulating CSF circulation and secrete BMP4 inhibiting noggin to modulate BMP signalling in the SVZ. BMP4 signalling through SMAD4 is important for neural specification of neuroblasts but does not influence further neuroblastic differentiation. It does appear to have a prosurvival effect on neuroblasts committed to the neuronal lineage. BMP4 signalling can promote astrogliogenesis from adult NSCs, but only with concomitant STAT-signalling, typically seen in CNS injury models. Recent evidence has shown that adult astrogliogenesis can occur from nestin+ SVZ NPCs, but the role of BMP4 in this process was not investigated. The role of BMP4 in OPC specification during development and adulthood is not completely resolved, but most data suggest that it does not play a significant role. However, there is a very clear inhibitory BMP4 effect on OPC progression towards an oligodendrocyte lineage during development, adulthood and CNS injury.

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