Sox9 function in craniofacial development and disease

Abstract

The Sox family of transcriptional regulators has been implicated in the control of a broad array of developmental processes. One member of this family SOX9 was first identified as a candidate gene for campomelic dysplasia (CD), a human syndrome affecting skeletal, and testis development. In these patients most endochondral bones of the face fail to develop resulting in multiple defects such as micrognathia, cleft palate, and facial dysmorphia. In this review we describe Sox9 expression during embryonic development and summarize loss of function experiments in frog, fish, and mouse embryos highlighting the role of Sox9 in regulating morphogenesis of the face. We also discuss the mutations in and around SOX9 responsible for craniofacial defects in CD patients.

Figure 1. Pattern of cranial neural cell migration and their skeletal derivatives

In the mammalian embryo neural crest cells delaminate from the posterior midbrain and individual rhombomeres (R1–R7) in the hindbrain, and migrate into the pharyngeal arches (PA). Neural crest cells migrate in a stereotypical pattern based on their origin in the hindbrain (arrows). In each arch the neural crest contributes a specific set of skeletal elements as indicated. The first pharyngeal arch has two parts the maxillary (MX) and mandibular (MD) prominences. The most caudal pharyngeal arches form laryngeal cartilages. Lateral view, anterior to left, dorsal to top. ov, otic vesicle.

Figure 2. Developmental expression of Xenopus Sox9 in the neural crest lineage

(A) By in situ hybridization, at the end of gastrulation Sox9 is detected in neural crest progenitors (nc) at the lateral edge of the neural plate (np), and in the presumptive otic placode (op). Dorsal view, anterior to left. (B) At the tailbud stage Sox9 is detected in the four streams of cranial neural crest migrating towards the pharyngeal arches, the mandibular (ma), hyoid (hy), anterior branchial (ab) and posterior branchial (pb) neural crest. Other domains of expression include the developing eye (ey) and the otic vesicle (ov). Lateral view, anterior to left, dorsal to top. (C) Sox9 expression in the head region of a stage 35 embryo (Nieuwkoop and Faber, 1967). Lateral view, anterior to left, dorsal to top. The black lines indicate the level of the sections shown in the subsequent panels. (D–E) Sections showing Sox9 expression in the mesenchyme of the pharyngeal arches. (F) Diagram of a stage 40 embryo, after Nieuwkoop and Faber (1967). Lateral view, anterior to left, dorsal to top. The red lines indicate the level of the sections shown in the subsequent panels. (G–H) Sox9 is detected in all differentiating cartilage elements, including the palatoquadrate (pq), ceratobranchial (cb), ceratohyal (ce) and Meckel's cartilage (not shown). br, brain; he, heart; ph, pharynx; st, future stomodeum.

Figure 3. Diagram illustrating the craniofacial defects observed in Sox9;Wnt1-Cre mouse embryos

(A) Diagram showing the paraxial mesoderm (red) and neural crest (blue) contribution to the mouse head skeleton. Lateral view, anterior to right. Als, Alisphenoid; Bs, Basisphenoid; Ex, Exooccipital; Nc, Nasal capsule; Os, Orbitosphenoid; So, Supraoccipital; Sq, Squamosal (modified from Noden and Schneider, 2006). (B) Sox9;Wnt1-Cre mouse embryos have a domed skull, a short snout and short mandibles. In these animals the missing skeletal elements of neural crest origin are depicted in white.