期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2103087118
关键词
skeletal innervation; TrkA; calvarial bone; cranial suture; spatial transcriptomics
资金
- NIH [AR068934, DE027922]
- Senior Research Career grant from the Veterans Administration
- National Eye Institute [K99 EY031742]
Sensory nerve-derived signals, including FSTL1, play a crucial role in coordinating cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.
The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here, we show the genetic inhibition of tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation and increased mineralization. In vitro, axons from peripheral afferent neurons derived from dorsal root ganglions (DRGs) of wild-type mice induce MPC proliferation in a spatially restricted manner via a soluble factor when cocultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in bone morphogenetic protein (BMP) and TGF-beta signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies, following direct, axonal coculture with MPCs, confirmed the alterations in BMP/TGF-beta signaling pathway transcripts. Among these, the BMP inhibitor follistatin-like 1 (FSTL1) replicated key features of the neural-to bone influence, including mitogenic and anti-osteogenic effects via the inhibition of BMP/TGF-beta signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.
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