Mechanisms of growth plate patterning revealed by natural variation in mammalian ossification

This research investigates how and why growth plates form at specific skeletal locations. Growth plates are localized regions of cartilage containing pools of chondrocytes that drive rapid bone elongation, yet the inductive signals and positional rules that determine where growth plates arise remain poorly understood. This project uses naturally occurring contrasts in ossification—paired skeletal elements that are otherwise equivalent but differ in whether they form a growth plate—to isolate the patterns of gene expression and chromatin regulation that control growth plate induction. Key model comparisons include metatarsal bones that form a growth plate at only one end, and the pisiform and calcaneus, which are unique within the wrist and ankle, respectively, in producing growth plates.

The pisiform is particularly informative because it is highly susceptible to perturbations of developmental genes, allowing investigators to link genetic perturbation phenotypes with mechanistic roles in growth plate formation. The research combines comparative developmental biology with cutting-edge genomics. By performing whole transcriptome (RNA-seq) and chromatin accessibility (ATAC-seq) profiling on paired growth plate-forming and non-forming tissues (pisiform, calcaneus, and metatarsal), the team aims to identify inductive factors and regulatory elements associated with growth plate initiation. The central hypothesis is that expression differences in chondrocyte populations precede the visible formation of growth plates and that these differences will be reflected in both reserve zone and perichondrial cell populations. In addition to broad, unbiased discovery, the project targets the role of Hox genes—particularly Hoxa11 and Hoxd11—in patterning. Although many carpals and tarsals develop as nodular elements with a limited Hox contribution, loss-of-function of Hox11 genes produces malformations in proximal carpals and tarsals including shortened pisiforms, suggesting a later-stage role for Hox11 in growth plate induction.

The team predicts that Hox11 directly helps establish reserve zone and perichondrial chondrocyte populations and that active enhancers containing Hox11-13 response elements will be enriched at growth plate-forming sites, with shared enhancer activity patterns across different growth plates. Beyond fundamental discovery, the project emphasizes training and outreach. The program expands laboratory research opportunities for a diverse cohort of undergraduate and graduate students, exposing them to contemporary methods in developmental biology and comparative genomics. It also supports collaborations with the College of Physicians of Philadelphia to develop outreach for underserved communities, including a science workshop that provides classroom and research experiences for gifted but underserved Philadelphia high school students. Funded by an $800,000 award from the National Science Foundation and spanning multiple years, this integrative effort seeks to elucidate the molecular and regulatory logic of growth plate patterning, with implications for understanding skeletal development, congenital differences in ossification, and the evolutionary diversification of limb morphology.