Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis

Area of Science:

• Developmental Biology
• Genetics
• Craniofacial Development

Background:

• Cleft palate is a frequent congenital malformation.
• Mutations in Sonic Hedgehog (SHH) signaling pathways are implicated in cleft palate.
• The gene regulatory networks downstream of Hedgehog (Hh) signaling are not fully understood.

Purpose of the Study:

• To investigate the downstream gene regulatory networks of Hh signaling in secondary palate development.
• To elucidate the mechanisms by which Hh signaling influences palatal bone formation and patterning.
• To identify key transcription factors and signaling pathways regulated by Hh.

Main Methods:

• Ectopic Hh signaling was induced in the palatal mesenchyme.
• Analysis of oral-nasal patterning of neural crest-derived ectomesenchyme.
• Investigation of Fox transcription factors and Wnt/BMP antagonists, including Sostdc1.
• Assessment of osteogenesis and BMP signaling effectors.

Main Results:

• Ectopic Hh signaling disrupted palatal shelf patterning and led to cleft palate.
• Fox transcription factors, including Foxl1, were identified as downstream targets of Hh signaling.
• Hh signaling positively regulated Wnt/BMP antagonists like Sostdc1.
• Hh signaling downregulated osteogenesis regulators and BMP signaling effectors.

Conclusions:

• Ectopic Hh signaling disrupts craniofacial development, causing cleft palate.
• Hh signaling regulates key transcription factors and antagonists in palate development.
• Hh-Smo signaling downregulates Wnt/BMP pathways, partly via Sostdc1, leading to defective osteogenesis and cleft palate.