Normal facial morphogenesis involves the precise spatiotemporal choreography of independent facial prominences that together must grow, contact, and fuse to form a functional upper jaw. The complexity of this process yields multiple ways in which it may go awry, so it is unsurprising that cleft lip (CL) has both a diverse etiology, and is also one of the most common human birth defects (~1:500-2500 births). Of the potential causes of CL, those that impact facial prominence growth are thought to play an outsized role since later events like contact and fusion are critically dependent on its success. That said, modeling growth has proven to be difficult because of the complex nature of tissue movements in space and time. In this grant we take a novel approach to the challenge of modeling facial prominence growth by combining innovative imaging protocols with three-dimensional geometric morphometric analyses of shape. With these tools we build novel ?developmental morphospace? model of 3D embryonic craniofacial morphogenesis in the mouse and chick and use it to generate in silico predictions of how growth variation impacts the phenotypic landscape of contact and fusion events, both normal and abnormal. We next experimentally modulate facial prominence and brain growth to directly test these model predictions in vivo. Support of DM predictions would validate a priori predictions of the effect of heterogeneous genetic mutational or environmental effects on CL-liability. Moreover, the DM would provide a generalized model for predicting how perturbations to facial prominence shape variability, growth trajectory, and brain size can combine to impact a range of contact and fusion events.
Cleft lip (CL) is one of the most common human structural birth defects, yet our ability to predict how any given genetic mutation or environmental factor might contribute to CL-incidence and severity has been limited by the challenging nature of modeling facial morphogenesis. In this grant our approach to this challenge is to utilize an innovative ?developmental morphospace? (DM) model of facial morphogenesis to test key in silico predictions with in vivo experimental outcomes. If validated, the DM model provides a valuable framework for predicting a priori how disparate factors impacting face and brain growth will contribute to influence CL-liability in humans. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
