Nuclear receptor Nr5a2 promotes diverse connective tissue fates in the jaw.

Organ development involves the sustained production of diverse cell types with spatiotemporal precision. In the vertebrate jaw, neural-crest-derived progenitors produce not only skeletal tissues but also later-forming tendons and salivary glands. Here we identify the pluripotency factor Nr5a2 as essential for cell-fate decisions in the jaw.

Development and maintenance of tendons and ligaments.

Tendons and ligaments are fibrous connective tissues vital to the transmission of force and stabilization of the musculoskeletal system. Arising in precise regions of the embryo, tendons and ligaments share many properties and little is known about the molecular differences that differentiate them. Recent studies have revealed heterogeneity and plasticity within tendon and ligament cells, raising questions regarding the developmental mechanisms regulating tendon and ligament identity.

FGF signaling patterns cell fate at the interface between tendon and bone.

Tendon and bone are attached by a transitional connective tissue that is morphologically graded from tendinous to osseous and develops from bipotent progenitors that co-express scleraxis (Scx) and Sox9 (Scx/Sox9). Scx/Sox9 progenitors have the potential to differentiate into either tenocytes or chondrocytes, yet the developmental mechanism that spatially resolves their bipotency at the tendon-bone interface during embryogenesis remains unknown. Here, we demonstrate that development of Scx/Sox9 progenitors within the mammalian lower jaw requires FGF signaling.

Nuclear FGFR2 regulates musculoskeletal integration within the developing limb.

Background: Bent bone dysplasia syndrome (BBDS), a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2), is characterized by bowed long bones within the limbs. We previously showed that the FGFR2 mutations in BBDS enhance nuclear and nucleolar localization of the receptor; however, exactly how shifts in subcellular distribution of FGFR2 affect limb development remained unknown.

Results: Targeted expression of the BBDS mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, a hallmark feature of the disease.

A requirement for Fgfr2 in middle ear development.

The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss.

Modeling craniofacial and skeletal congenital birth defects to advance therapies.

Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes.