Ciliary Hedgehog signaling regulates cell survival to build the facial midline

Area of Science:

• Developmental Biology
• Genetics
• Craniofacial Development

Background:

• Craniofacial defects are common in ciliopathies, but their causes are unclear.
• Ciliopathies disrupt cellular functions, impacting embryonic development.
• Hypotelorism (midface narrowing) is a frequent phenotype in ciliopathies.

Purpose of the Study:

• Investigate the molecular basis of craniofacial defects in ciliopathies.
• Determine the role of Hedgehog (HH) signaling in midface development.
• Identify therapeutic targets for ciliopathy-associated craniofacial abnormalities.

Main Methods:

• Examined mouse models of human ciliopathies (Tctn2, Cc2d2a, Tmem231 mutants).
• Assessed Hedgehog (HH) pathway activation in prechordal plate and neurectoderm.
• Analyzed cell death and midface morphology.
• Manipulated HH pathway signaling using Ptch1 gene dosage.

Main Results:

• Ciliopathy mouse models exhibited hypotelorism and reduced HH pathway activation.
• Defects in the prechordal plate preceded reduced HH signaling in the neurectoderm.
• Reduced HH signaling led to increased cell death and midface collapse.
• Enhancing HH signaling rescued midface defects and reduced cell death.

Conclusions:

• Ciliary HH signaling is crucial for communication between the prechordal plate and neurectoderm.
• This signaling provides essential survival cues for facial midline development.
• Targeting HH pathway can potentially treat ciliopathy-related craniofacial defects.