Fgf8 regulates first pharyngeal arch segmentation through pouch-cleft interactions.

Introduction: The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Formation of ectodermal-endodermal interfaces is a key mediator of this process, and although it is essential, mechanisms regulating the establishment of these interfaces vary between pouches and between taxa. Methods: Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes in the mouse model system. Results: We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Discussion: Based on Fgf8-mediated changes in tissue relationships between pp1 and pc1, we hypothesize that extension of pp1 requires physical interaction with pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.

Fgf8 regulates first pharyngeal arch segmentation through pouch-cleft interactions.

The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Out-pocketing of the pharyngeal endoderm between the arches is a key mediator of this process, and although it is essential, mechanisms regulating out-pocketing vary between pouches and between taxa. Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes. We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that extension of pp1 requires physical interaction with pc1, and that multiple aspects of pc1 morphogenesis require Fgf8 . In particular, Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.

Fgf8 dosage regulates jaw shape and symmetry through pharyngeal-cardiac tissue relationships.

BACKGROUND: Asymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. RESULTS: Developmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-specimen variation. CONCLUSIONS: We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.