A review of hedgehog signaling in cranial bone development

Angel Pan,Aaron W James,Alan Nguyen,Le Chang

doi:10.3389/fphys.2013.00061

Abstract

During craniofacial development, the Hedgehog (HH) signaling pathway is essential for mesodermal tissue patterning and differentiation. The HH family consists of three protein ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH), of which two are expressed in the craniofacial complex (IHH and SHH). Dysregulations in HH signaling are well documented to result in a wide range of craniofacial abnormalities, including holoprosencephaly (HPE), hypotelorism, and cleft lip/palate. Furthermore, mutations in HH effectors, co-receptors, and ciliary proteins result in skeletal and craniofacial deformities. Cranial suture morphogenesis is a delicate developmental process that requires control of cell commitment, proliferation and differentiation. This review focuses on both what is known and what remains unknown regarding HH signaling in cranial suture morphogenesis and intramembranous ossification. As demonstrated from murine studies, expression of both SHH and IHH is critical to the formation and fusion of the cranial sutures and calvarial ossification. SHH expression has been observed in the cranial suture mesenchyme and its precise function is not fully defined, although some postulate SHH to delay cranial suture fusion. IHH expression is mainly found on the osteogenic fronts of the calvarial bones, and functions to induce cell proliferation and differentiation. Unfortunately, neonatal lethality of IHH deficient mice precludes a detailed examination of their postnatal calvarial phenotype. In summary, a number of basic questions are yet to be answered regarding domains of expression, developmental role, and functional overlap of HH morphogens in the calvaria. Nevertheless, SHH and IHH ligands are integral to cranial suture development and regulation of calvarial ossification. When HH signaling goes awry, the resultant suite of morphologic abnormalities highlights the important roles of HH signaling in cranial development.

Highlights

Craniofacial morphogenesis, an intricate developmental process, begins with the synchronized development of head primordia, which involves several organizing centers located in the neural ectoderm, axial mesendoderm, and the cranial neural crest
Dysregulation of the Hedgehog (HH) signaling pathway results in a wide array of craniofacial defects including holoprosencephaly (HPE), hypotelorism, and cyclopia, amongst others (Belloni et al, 1996). Both Indian Hedgehog (IHH) and Sonic Hedgehog (SHH) have been well studied in cartilage and bone patterning throughout the axial, appendicular and facial skeleton (Hammerschmidt et al, 1997; Capdevila and Johnson, 2000; Chai and Maxson, 2006)
The role of HH signaling in calvarial ossification and cranial suture morphogenesis is a relatively new and less examined area of scientific investigation

Summary

INTRODUCTION

Craniofacial morphogenesis, an intricate developmental process, begins with the synchronized development of head primordia, which involves several organizing centers located in the neural ectoderm, axial mesendoderm, and the cranial neural crest. Mutations in the IFT protein DYNC2H1, causes short rib polydactyly syndrome, a lethal autosomal recessive condition that features cerebral and skeletal abnormalities, such as HPE, in addition to other appendicular malformations (Dagoneau et al, 2009; Merrill et al, 2009; El Hokayem et al, 2012) Mutations in another IFT protein, IFT144, result in craniofacial anomalies such as craniosynostosis and exencephaly, which results from deficient ciliogenesis and diminished response to upstream activation of HH signaling (Ashe et al, 2012). Cilia are involved in the regulation of HH signal transduction, the precise mechanisms of this relationship are only partially elucidated Another potential cause of craniofacial abnormalities includes exposure to teratogens, which interfere with the HH signaling pathway. The steroidal alkaloid Cyclopamine (11-deoxojervine) causes teratogenic effects through direct binding of cyclopamine to the SMO

Transcriptional repressor of HH signaling

CDO BOC

Findings

CONCLUSIONS