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Single-cell profiling of penta- and tetradactyl mouse limb buds identifies mesenchymal progenitors controlling digit numbers and identities

Author

Listed:
  • Victorio Palacio

    (University of Basel)

  • Anna Pancho

    (University of Basel)

  • Angela Morabito

    (University of Basel)

  • Jonas Malkmus

    (University of Basel)

  • Zhisong He

    (ETH Zürich)

  • Geoffrey Soussi

    (University of Basel)

  • Rolf Zeller

    (University of Basel)

  • Barbara Treutlein

    (ETH Zürich)

  • Aimée Zuniga

    (University of Basel)

Abstract

The cellular interactions controlling digit numbers and identities have remained largely elusive. Here, we leverage the anterior digit and identity loss in Grem1 tetradactyl mouse limb buds to identify early specified limb bud mesenchymal progenitor (LMP) populations whose size and distribution is governed by spatial modulation of BMP activity and SHH signaling. Distal-autopodial LMPs (dLMP) express signature genes required for autopod and digit development, and alterations affecting the dLMP population size prefigure the changes in digit numbers that characterize specific congenital malformations. A second, peripheral LMP (pLMP) population is anteriorly biased and reduction/loss of its asymmetric distribution underlies the loss of middle digit asymmetry and identities in Grem1 tetradactyl and pig limb buds. pLMPs depend on BMP activity, while dLMPs require GREM1-mediated BMP antagonism. Taken together, the spatial alterations in GREM1 antagonism in mouse mutant and evolutionarily diversified pig limb buds tunes BMP activity, which impacts dLMP and pLMP populations in an opposing manner.

Suggested Citation

  • Victorio Palacio & Anna Pancho & Angela Morabito & Jonas Malkmus & Zhisong He & Geoffrey Soussi & Rolf Zeller & Barbara Treutlein & Aimée Zuniga, 2025. "Single-cell profiling of penta- and tetradactyl mouse limb buds identifies mesenchymal progenitors controlling digit numbers and identities," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56221-1
    DOI: 10.1038/s41467-025-56221-1
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    References listed on IDEAS

    as
    1. Francesca V. Mariani & Christina P. Ahn & Gail R. Martin, 2008. "Genetic evidence that FGFs have an instructive role in limb proximal–distal patterning," Nature, Nature, vol. 453(7193), pages 401-405, May.
    2. Kimberly L. Cooper & Karen E. Sears & Aysu Uygur & Jennifer Maier & Karl-Stephan Baczkowski & Margaret Brosnahan & Doug Antczak & Julian A. Skidmore & Clifford J. Tabin, 2014. "Patterning and post-patterning modes of evolutionary digit loss in mammals," Nature, Nature, vol. 511(7507), pages 41-45, July.
    3. Aimée Zúñiga & Anna-Pavlina G. Haramis & Andrew P. McMahon & Rolf Zeller, 1999. "Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds," Nature, Nature, vol. 401(6753), pages 598-602, October.
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