Evidence map›Paper›PMID 34663698›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2021

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 and 3 more

Open access · greenAbstract read
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed
8.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

55 citing papers in PubMed, 74 citations in OpenAlex.

  1. Article
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  5. Article
  6. Review
  7. Review
  8. Article
  9. Advances in Spatial Transcriptomics in Bone.Current osteoporosis reports · 2026
    Review
  10. Article
  11. Article
  12. Review
  13. Article
  14. The nerve center of organ engineering.Nature communications · 2025
    Review
  15. Review
  16. Single-cell sequencing uncovers sensory neuron-mediated CGRP signaling as a driver of sarcoma progression.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 2 institutions in 1 country.

Robert J TowerDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205.ORCID 0000-0001-5856-5758
Zhu LiDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205.
Yu-Hao ChengDepartment of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205.ORCID 0000-0002-7472-8518
Xue-Wei WangDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205.ORCID 0000-0002-1375-7358
Labchan RajbhandariDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21287.ORCID 0000-0002-9252-2580
Qian ZhangDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205.ORCID 0000-0003-3032-9088
Stefano NegriDepartment of Pathology, Johns Hopkins University, Baltimore, MD 21205.ORCID 0000-0003-2218-6654
Cedric R UytingcoDepartment of Molecular Biology, 10X Genomics, Pleasanton, CA 94588.
Arun VenkatesanDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21287.
Feng-Quan ZhouDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205.ORCID 0000-0002-1525-9969
Patrick CahanDepartment of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205.ORCID 0000-0003-3652-2540
Aaron W JamesDepartment of Pathology, Johns Hopkins University, Baltimore, MD 21205; tclemen5@jhmi.edu awjames@jhmi.edu.ORCID 0000-0002-2002-622X
Thomas L ClemensDepartment of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21205; tclemen5@jhmi.edu awjames@jhmi.edu.
Johns Hopkins University · USUnited States Department of Veterans Affairs · US

Funding

Neuronal Regulation of Skeletal Development and RepairR01DE031028 · NIDCR · UNIVERSITY OF MARYLAND BALTIMORE · PI CLEMENS, THOMAS L, JAMES, AARON W · 2021 to 2025
$2.3M
Reprogramming retinal ganglion cells for optic nerve regeneration and guidanceR01EY027347 · NEI · JOHNS HOPKINS UNIVERSITY · PI CAO, XU · 2017 to 2021
$2.0M
Targeting aging genes and pathways to promote optic nerve regenerationR01EY030883 · NEI · JOHNS HOPKINS UNIVERSITY · PI WAN, MEI · 2020 to 2024
$2.0M
Neuronal Regulation of Skeletal Development and RepairR01AR068934 · NIAMS · JOHNS HOPKINS UNIVERSITY · PI CLEMENS, THOMAS L · 2015 to 2019
$1.8M
Remodeling of chromatin and transcriptomic landscape to enhance optic nerve regenerationR01EY031779 · NEI · JOHNS HOPKINS UNIVERSITY · PI QIAN, JIANG · 2020 to 2023
$1.7M
PTH-RELATED PROTEIN IN VASCULAR SMOOTH MUSCLER01HL047811 · NHLBI · UNIVERSITY OF CINCINNATI · PI CLEMENS, THOMAS L · 1993 to 2004
$1.6M
Role of sensory nerves in cranial bone repairR21DE027922 · NIDCR · JOHNS HOPKINS UNIVERSITY · PI CLEMENS, THOMAS L, JAMES, AARON W · 2018 to 2019
$450k
Deciphering the Transcriptional Regulatory Network Controlling RGC Axon Growth to Promote RGC Axon Regeneration and Cell Survival after Axonal InjuryK99EY031742 · NEI · JOHNS HOPKINS UNIVERSITY · PI WANG, XUEWEI · 2020 to 2023
$326k
BLRD VA IK6 BX004984NEI NIH HHS K99 EY031742NEI NIH HHS R01 EY027347NEI NIH HHS R01 EY030883NEI NIH HHS R01 EY031779NHLBI NIH HHS R01 HL047811NIAMS NIH HHS R01 AR068934NIDCR NIH HHS R01 DE031028NIDCR NIH HHS R21 DE027922
6 · The paper itself

Abstract

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.

Indexed as

Signal TransductionTranscriptomeAnimalsBone Morphogenetic ProteinsCranial SuturesMiceNervous SystemTransforming Growth Factor betaBone Morphogenetic ProteinsTransforming Growth Factor betacalvarial bonecranial sutureskeletal innervationspatial transcriptomicsTrkA

Identifiers

PMID34663698
PMCPMC8545472
OpenAlexW3206795626

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.