Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGF-β signaling

Robert J. Tower, Zhu Li, Yu Hao Cheng, Xue Wei Wang, Labchan Rajbhandari, Qian Zhang, Stefano Negri, Cedric R. Uytingco, Arun Venkatesan, Feng Quan Zhou, Patrick Cahan, Aaron W. James, Thomas L. Clemens

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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-β 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-β 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-β 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.

Original languageEnglish (US)
Article numbere2103087118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
StatePublished - Oct 19 2021
Externally publishedYes


  • TrkA
  • calvarial bone
  • cranial suture
  • skeletal innervation
  • spatial transcriptomics

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGF-β signaling'. Together they form a unique fingerprint.

Cite this