Comparative morphometrics of embryonic facial morphogenesis: implications for cleft-lip etiology.

Cleft lip (CL) with or without cleft palate (CL[P]) has a complex etiology but is thought to be due to either genetic or environmentally induced disruptions of developmental processes affecting the shape and size of the facial prominences (medial nasal, lateral nasal, and maxilla). Recent advances in landmark-based morphometrics enable a rigorous reanalysis of phenotypic shape variation associated with facial clefting. Here we use geometric morphometric (GM) tools to characterize embryonic shape variation in the midface and head of six strains of mice that are both cleft-liable (A, A/WySn, CL/Fr) and normal (BALB/cBy, C57BL, CD1). Data were comprised of two-dimensional landmarks taken from frontal and lateral photographs of embryos spanning the time period in which the facial prominences fuse (GD10-12). Results indicate that A/- strain mice, and particularly A/WySn, have overall smaller midfaces compared to other strains. The A/WySn strain also has significant differences in facial shape related to retarded development. Overall, CL/Fr strain mice are normal-sized, but tend to have undersized maxillary prominences that do not project anteriorly and have a small nasal contact area. These results suggest that the etiology of clefting differs in A/WySn and CL/Fr strains, with the former strain suffering disruptions to developmental processes affecting overall size (e.g., neural crest migration deficiencies and lower mitotic activity), while the latter strain has defects restricted to the shape and size of the maxilla. A combination of molecular experimentation and phenotypic analysis of shape is required to test these hypotheses further.