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Peer-reviewedCC BY 4.0Proceedings of the National Academy of Sciences of the United States of America

Lhx9 specifically modulates phalanx number, whereas Lhx2 constrains digit length in tetrapods

  • Yining Tang1
  • Shibin Bai1,2
  • Shanshan Li1,2
  • Ying Mao1
  • Wanyi Dang1
  • Huiling Xue1
  • Songyang Shang1
  • Ziqiu Jia1
  • Xiaoping Li1
  • Yanlei Liu1
  • Xiaona Xu1
  • David M. Irwin3
3 more authors
  • Junpeng Zhang1
  • Shuyi Zhang1
  • Zhe Wang1
  1. 1College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China
  2. 2School of Basic Medical Science, Chengde Medical University, Chengde 067000, Hebei, China
  3. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
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Abstract

Most nonmammalian tetrapods exhibit more than three phalanges in their posterior digits (III–V), whereas mammals are restricted to no more than three. So far, the molecular mechanism underlying this evolutionary reduction and the functions of Lhx2 and Lhx9 in digit development remain unclear. Here we show divergent evolution of Lhx2 and Lhx9 expression patterns in embryonic limbs across tetrapods. We further demonstrate that although ectopic overexpression of each gene in chick embryos delayed limb skeletal development, only Lhx9 reduced the phalanx number in the posterior digits. Transcriptomic analysis showed that Lhx2 regulates pathways for chondrocyte and osteoblast differentiation, and Lhx9 preferentially influences skeletal segmentation via the bone morphogenetic protein (BMP) pathway. The unique function and differential expression of Lhx9 in the limb buds between mammals and nonmammalian tetrapods suggest it may have acquired a role in suppressing phalanx number, driving the evolutionary reduction of phalanx number in mammals.

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Cite

BibTeXRIS
BibTeX
@article{tang2026lhx9,
  title = {{Lhx9 specifically modulates phalanx number, whereas Lhx2 constrains digit length in tetrapods}},
  author = {Yining Tang and Shibin Bai and Shanshan Li and Ying Mao and Wanyi Dang and Huiling Xue and Songyang Shang and Ziqiu Jia and Xiaoping Li and Yanlei Liu and Xiaona Xu and David M. Irwin and Junpeng Zhang and Shuyi Zhang and Zhe Wang},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2605261123},
  url = {https://doi.org/10.1073/pnas.2605261123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lhx9 specifically modulates phalanx number, whereas Lhx2 constrains digit length in tetrapods
AU  - Yining Tang
AU  - Shibin Bai
AU  - Shanshan Li
AU  - Ying Mao
AU  - Wanyi Dang
AU  - Huiling Xue
AU  - Songyang Shang
AU  - Ziqiu Jia
AU  - Xiaoping Li
AU  - Yanlei Liu
AU  - Xiaona Xu
AU  - David M. Irwin
AU  - Junpeng Zhang
AU  - Shuyi Zhang
AU  - Zhe Wang
PY  - 2026
DA  - 2026/10/20
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2605261123
UR  - https://doi.org/10.1073/pnas.2605261123
AB  - Most nonmammalian tetrapods exhibit more than three phalanges in their posterior digits (III–V), whereas mammals are restricted to no more than three. So far, the molecular mechanism underlying this evolutionary reduction and the functions of Lhx2 and Lhx9 in digit development remain unclear. Here we show divergent evolution of Lhx2 and Lhx9 expression patterns in embryonic limbs across tetrapods. We further demonstrate that although ectopic overexpression of each gene in chick embryos delayed limb skeletal development, only Lhx9 reduced the phalanx number in the posterior digits. Transcriptomic analysis showed that Lhx2 regulates pathways for chondrocyte and osteoblast differentiation, and Lhx9 preferentially influences skeletal segmentation via the bone morphogenetic protein (BMP) pathway. The unique function and differential expression of Lhx9 in the limb buds between mammals and nonmammalian tetrapods suggest it may have acquired a role in suppressing phalanx number, driving the evolutionary reduction of phalanx number in mammals.
SN  - 0027-8424
SN  - 1091-6490
ER  -