2. Academic Validation
  3. DLX2 acts as a pioneer factor and drives Msx1+ ectomesenchyme formation from embryonic stem cells

DLX2 acts as a pioneer factor and drives Msx1+ ectomesenchyme formation from embryonic stem cells

  • Sci Adv. 2026 Jan 16;12(3):eaea0685. doi: 10.1126/sciadv.aea0685.
Ziwei Zhang 1 2,  Zhiheng Xu 1,  Hong Hu 1 3,  Yao Li 4,  Youmei Jin 5,  Yi Zhong 5,  Yunqiu Zhang 1 2,  Yike Yin 1,  Jing Chen 4,  Yufeng Duan 6,  Hao Yang 5,  Zhonghan Li 1 2 7
Affiliations

Affiliations

  • 1 Center of Growth Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610065, China.
  • 2 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610041, China.
  • 3 College of Basic Medical Sciences and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China.
  • 4 Department of Pediatric Surgery and Laboratory of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Liver Surgery and NHC Key Lab of Transplant Engineering and Immunology, Proteomics-Metabolomics Platform of Core Facilities, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6 Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai 200011, China.
  • 7 Yunnan Key Laboratory of Stomatology, Department of Pediatric Dentistry, The Affiliated Stomatology Hospital of Kunming Medical University, Kunming Medical University, Kunming 650500, China.
PMID: 41533791 DOI: 10.1126/sciadv.aea0685
Abstract

The ectomesenchyme generates much of the craniofacial skeleton, sutures, and diverse connective tissues in the mammalian head, yet its derivation from embryonic stem cells (ESCs) and the underlying molecular drivers remain poorly defined. Here, we identified Dlx2 as a key regulator that efficiently directed murine ESCs toward Msx1+ ectomesenchyme, recapitulating the developmental trajectory. These Msx1+ progenitors expressed classical craniofacial markers, exhibited robust osteochondral differentiation potential as a group, and supported craniofacial regeneration. Mechanistically, Distal-less homeobox 2 (DLX2) formed a complex with lamina-associated polypeptide 2, isoform alpha (LAP2α) through a 38-amino-acid homeodomain motif, interacting with nucleosomes to promote chromatin remodeling and activate a procraniofacial ectomesenchymal gene network. Disrupting DLX2-LAP2α interaction or silencing Dlx2 targets markedly diminished ectomesenchymal differentiation. Our findings established DLX2 as a pioneer factor in ectomesenchyme specification, offering insights into craniofacial development and stem cell engineering.

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