Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions.

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• The choroid plexus epithelium, featuring multiciliated cells, is crucial for cerebrospinal fluid (CSF) production.
• Cilia dysfunction is linked to various neurological disorders, including hydrocephalus.

Purpose of the Study:

• To investigate the role of choroid plexus multicilia in regulating CSF production and their connection to hydrocephalus.
• To elucidate the signaling pathways involved in choroid plexus ciliary function and development.

Main Methods:

• Analysis of choroid plexus ciliogenesis and intraflagellar transport in a neonatal hydrocephalus model.
• Examination of Aqp1 and Atp1a2 expression in relation to ciliary function.
• Investigation of Sonic Hedgehog (Shh) signaling pathways, including non-canonical pathways involving Smoothened (Smo)/Gαi/cyclic AMP (cAMP).

Main Results:

• Defective choroid plexus ciliogenesis or intraflagellar transport leads to neonatal hydrocephalus.
• This condition is associated with increased expression of the water channel Aqp1 and ion transporter Atp1a2.
• Choroid plexus multicilia function as sensory cilia, transducing Shh signaling, with non-canonical Shh repressing Aqp1 and Atp1a2 via the Smo/Gαi/cAMP pathway.
• Developmental shortening of choroid plexus cilia reduces Shh signaling, derepresses Aqp1 and Atp1a2, and increases CSF production.

Conclusions:

• Choroid plexus multicilia play a critical sensory role in regulating CSF production through Shh signaling.
• The unique developmental dynamics of these cilia, specifically their decreasing length, actively dampen Shh signaling to promote CSF production.
• Understanding these mechanisms offers insights into hydrocephalus pathogenesis and potential therapeutic targets.