BMPR1a and BMPR1b Signaling Exert Opposing Effects on Gliosis after Spinal Cord Injury

Abstract

Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that is beneficial and a subsequent formation of a dense scar. We investigated the role of bone morphogenetic protein (BMP) signaling in gliosis after SCI and find that BMPR1a and BMPR1b signaling exerts opposing effects on hypertrophy. Conditional ablation of BMPR1a from glial fibrillary acidic protein (GFAP)-expressing cells leads to defective astrocytic hypertrophy, increased infiltration by inflammatory cells, and reduced axon density. BMPR1b-null mice conversely develop “hyperactive” reactive astrocytes and consequently have smaller lesion volumes. The effects of ablation of either receptor are reversed in the double knock-out animals. These findings indicate that BMPR1a and BMPR1b exert directly opposing effects on the initial reactive astrocytic hypertrophy. Also, BMPR1b knock-out mice have an attenuated glial scar in the chronic stages following injury, suggesting that it has a greater role in glial scar progression. To elucidate the differing roles of the two receptors in astrocytes, we examined the effects of ablation of either receptor in serum-derived astrocytes in vitro. We find that the two receptors exert opposing effects on the posttranscriptional regulation of astrocytic microRNA-21. Further, overexpression of microRNA-21 in wild-type serum-derived astrocytes causes a dramatic reduction in cell size accompanied by reduction in GFAP levels. Hence, regulation of microRNA-21 by BMP signaling provides a novel mechanism for regulation of astrocytic size. Targeting specific BMPR subunits for therapeutic purposes may thus provide an approach for manipulating gliosis and enhancing functional outcomes after SCI.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…These results indicate a specific role of BMPRIA in the initial injury response; however, Bmpr1a 2/2 mice show better recovery 5 weeks postinjury, suggesting that BMPRIB regulates glial scar progression (Sahni et al 2010). Further, miR-21, a posttranscriptional regulator of gene expression induced by BMP signaling, mediates the astrocytic response after spinal cord injury (Sahni et al 2010;Bhalala et al 2012). Thus, many members of the TGF-b family have important roles following CNS injury, although these processes have yet to be fully understood.…”

“…Bmpr1b 2/2 mice have reduced lesion volumes and an increase in GFAP-expressing cells 1 week postinjury, whereas this result is not apparent in Bmpr1a 2/2 ; Bmpr1b 2/2 mice. These results indicate a specific role of BMPRIA in the initial injury response; however, Bmpr1a 2/2 mice show better recovery 5 weeks postinjury, suggesting that BMPRIB regulates glial scar progression (Sahni et al 2010). Further, miR-21, a posttranscriptional regulator of gene expression induced by BMP signaling, mediates the astrocytic response after spinal cord injury (Sahni et al 2010;Bhalala et al 2012).…”

“…However, there is evidence that BMP inhibition enhances axonal outgrowth and locomotor activity (Setoguchi et al 2004;Matsuura et al 2008). BMP receptor signaling following injury show a beneficial effect of BMPRIA, and not BMPRIB for wound repair (Sahni et al 2010). Bmpr1b 2/2 mice have reduced lesion volumes and an increase in GFAP-expressing cells 1 week postinjury, whereas this result is not apparent in Bmpr1a 2/2 ; Bmpr1b 2/2 mice.…”

p53 Regulates Neural Stem Cell Proliferation and Differentiation via BMP-Smad1 Signaling and Id1

“…Smad1/ 5/8 then associate with Smad4, move into the nucleus, and turn on BMP target genes. BMPs play various and sometimes distinct roles throughout the development of the nervous system, often in a context and stage dependent manner [10]. In mouse embryonic stem (ES) cells, BMPs act to inhibit neuronal differentiation and help self-renewal [11].…”

Oligodendrocyte Fate after Spinal Cord Injury

“…Sonic hedgehog, which is pro-oligogenic, is upregulated acutely in neurons and OLs after injury, and remains high for several weeks [72]. A rise in BMP and its cognate receptor was observed for 2 weeks after injury [72][73][74]. BMP can drive stem/progenitor cells toward an astrocyte rather than OL fate [75].…”