Regulation of early mandibular morphogenesis by the homeobox protein MSX1

Craniofacial anomalies are among the most common congenital conditions, significantly impacting patients' health and quality of life. To overcome the current challenges in preventing or treating these congenital disorders, we must first deepen our understanding of the underlying developmental mechanisms and gene functions. Mutations in the Msx1 (Msh Homeobox 1) gene, which encodes a transcriptional repressor, are associated with a range of craniofacial phenotypes in humans, including tooth agenesis, cleft palate, and shortened mandibles. Similarly, mouse embryos with Msx1 deletion exhibit comparable traits. In the developing mandibular arch, Msx1 is expressed in the distal domain and patterns the expression of downstream genes. However, these downstream gene targets are not fully identified, leaving open questions around the molecular and cellular mechanisms underlying Msx1 regulation of early mandibular morphogenesis. Using the Msx1 null mouse embryo, our preliminary studies found upregulation of proteoglycans and TGF-β signaling in the distal mandibular arch, while mitochondrial functions are compromised. Furthermore, since these pathways can modulate basic cell behaviors, we examined various cellular processes and found that Msx1 mutant mandibles exhibit reduced cell-cell adhesion, increased cell movements, and a more fluid-like tissue material property. These findings thus suggest a crucial, but previously unappreciated, mechanism by which Msx1-mediated patterning regulates cell-cell interactions and mitochondrial metabolism to control tissue mechanics and drive mandibular elongation. We have proposed 3 Aims to test this. In Aim 1, we will identify direct transcriptional targets of MSX1 and establish the spatial transcriptomic changes following Msx1 deletion, completing our understanding of MSX1's patterning role during mandible development. In Aim 2, we will map the spatial changes in tissue mechanics upon loss of Msx1 and determine the functional significance of the proteoglycan- TGF-β signaling axis in modulating the tissue unjamming process. Aim 3 investigates the role of mitochondrial function in maintaining cell adhesion and tissue rigidification to promote mandibular elongation. Together, these studies will deliver a mechanistic understanding of how tissues convert spatial patterning of gene expression into distinct cellular behaviors that control craniofacial morphogenesis, yielding findings that will be of general interest to developmental biologists and to the biomechanical and metabolic communities. Project Number: 1R01DE035572-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Jimmy Hu | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $449,886 | Activity Code: R01 | Study Section: Skeletal Biology Development and Disease Study Section[SBDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11280352