Signaling networks in palate development

Abstract

Palatogenesis, the formation of the palate, is a dynamic process regulated by a complex series of context-dependent morphogenetic signaling events. Many genes involved in palatogenesis have been discovered through the use of genetically manipulated mouse models as well as from human genetic studies, but the roles of these genes and their products in signaling networks regulating palatogenesis are still poorly known. In this review, we give a brief overview on palatogenesis and introduce key signaling cascades leading to formation of the intact palate. Moreover, we review conceptual differences between pathway biology and network biology and discuss how some of the recent technological advances in conjunction with mouse genetic models have contributed to our understanding of signaling networks regulating palate growth and fusion. For further resources related to this article, please visit the WIREs website.

Conflict of interest: The authors have declared no conflicts of interest for this article.

Fig. 1

Schematic representation of palatal growth and fusion. Palatal shelves (PS) can be first seen as outgrowths of the maxillary processes of the first pharyngeal arch (E11.5). They then grow vertically down along the sides of the tongue (T; E13.0), rapidly elevate (E14.0), form a contact with each other and with the nasal septum (NS) in the anterior palate (P) (E15.0) and eventually fuse (E16.0).

Fig. 2

Signaling circuits governing palatal shelf growth and patterning. A, Epithelial-mesenchymal interactions via Pax9-regulated Shh-Bmp and Shh-Fgf feed-back loops control growth and patterning of the anterior palate. B, Oro-nasal patterning of the anterior secondary palate is regulated via Fgf7-mediated Shh repression. C, Pax9-regulated expression of Bmp4 and Osr2 in the posterior palatal mesenchyme and Shh in the posterior palatal epithelium is required for appropriate posterior growth of the secondary palate. In addition, Meox2, Barx1 and Mn1-Tbx22 signaling module regulate posterior palatal growth. Grey, palatal mesenchyme; Green, palatal epithelium.

Fig. 3

A, Molecular control of palatal epithelial (green) differentiation. Fgf-Notch signaling, P63-Irf6 signaling, Tbx1 and Ikk-α regulate differentiation or the prefusion palatal epithelium (green). B, Medial edge epithelial loss is mediated via a signaling cascade involving TGF-β3, Irf6, p63 and p21in the palatal midline epithelial seam (green).

Fig. 4

Schematic comparison of a pathway biology model (A) to a network biology model (B). Arrows depict interactions between signaling molecules. In a pathway biology model (A), genomic information regulating a cell fate is mediated by a linear pathway, where every downstream function is directly affected by an upstream signaling molecule. In a network biology model, genomic information controlling a certain cell fate is mediated by a network of interacting molecules.