Pathogenesis of cleft lip and its relation to embryonic face shape in A/J and C57BL mice

Abstract

A comparison was made of early face embryology in the inbred A/J mouse strain with a spontaneous frequency of about 12% cleft lip and the C57BL/6J strain which virtually never has cleft lip. From the time of their appearance the medial nasal, lateral nasal and maxillary processes are connected by an isthmus. Subsequently there is fusion between the adjacent epithelia of medial and lateral nasal processes. Failure of this fusion, followed by breakdown of the isthmus, results in cleft lip. Just before and when the adjacent epithelia of medial nasal and lateral nasal processes meet and fuse at the posterior end of the nasal pit, the medial nasal processes of A/J embryos were more prominent, more medially placed, and diverged less than those of C57BL/6J. It is suggested that (a) cleft lip is a threshold character or quasi‐continuous variant such that a very slight change in the divergence of the medial nasals leads to their partial or complete lack of fusion with the lateral nasals. This is followed by a lack of fusion of medial and maxillary processes, and a complete or partial breakdown of the isthmus, resulting in a cleft lip; (b) the strain differences in type of aspirin‐induced cleft lip and in topography and growth of the facial processes between the two strains are causally related to the A/J predisposition to cleft lip.

Development of the upper lip: Morphogenetic and molecular mechanisms

“…4 in Senders et al, 2003). Studies in mouse embryos showed that fusion between the nasal processes occurred initially at the posterior part of the nasal pits and proceeded in an anterior direction (Trasler, 1968;Gaare and Langman, 1977a), similar to what Hinrichsen described for human embryonic face development (Hinrichsen, 1985).…”

“…Recently, Senders et al (2003) presented high resolution SEM pictures of developing cynomolgus monkey embryonic faces. Comparing these with other histological and SEM studies of facial development in mouse and chick (Trasler, 1968;Gaare and Langman, 1977a,b;Yee and Abbott, 1978;Millicovsky and Johnston, 1981;Millicovsky et al, 1982;Trasler and Ohannessian, 1983;Cox, 2004) provides an accurate understanding of the morphological processes involved in facial development.…”

“…2 in Cox, 2004). Trasler (1968) emphasized the importance of fusion between medial and lateral nasal processes and postulated that lateral cleft lip results when this fusion process does not occur. Ohbayashi and Eto (1986) carried out a microsurgical assay of relative contributions of the different facial processes in facial morphogenesis in rat embryos and found that surgical removal of either a lateral nasal or a maxillary process from one side of the face did not prevent fusion of the other process with the medial nasal process, whereas removal of the distal part of a medial nasal process resulted in cleft lip on the surgical side.…”

“…Whereas the union between the freely projected maxillary, lateral nasal, and medial nasal processes clearly involves active epithelial fusion, closure of the median groove between the paired medial nasal processes in mammals does not (Trasler, 1968;Millicovsky and Johnston, 1981;Millicovsky et al, 1982;Trasler and Ohannessian, 1983;Hinrichsen, 1985;Senders et al, 2003;Cox, 2004). As the epithelial fusion between maxillary, lateral nasal, and medial nasal processes continues from stage 16 to stage 18 (toward the beginning of the seventh week of gestation in human, The boundary between the maxillary and lateral nasal processes is clearly marked by the rounded cells at the surface.…”

“…Confusion exists in the literature with regard to the morphological processes leading to the formation of the intact upper lip. Whereas several studies describe that the upper lip forms from fusion between the maxillary and the medial nasal processes (e.g., Sun et al, 2000;Ashique et al, 2002;Sperber, 2002;Cox, 2004), others state that a cleft lip results when the epithelia of the opposing medial and lateral nasal processes fail to make contact (Trasler, 1968;Gaare and Langman, 1977a;Gong and Guo, 2003). The confusion may have arisen due in part to species differences (e.g., chick vs. mouse and human) in facial morphogenesis and in part to lack of synthesis of the fragmentary and often incomplete information gained from individual studies.…”