Multicilia dynamically transduce Shh 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.
• Dysfunctional cilia in the choroid plexus are linked to neurological conditions like 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 and molecular mechanisms underlying choroid plexus ciliogenesis and function.

Main Methods:

• Analysis of choroid plexus ciliogenesis and intraflagellar transport in relation to hydrocephalus.
• Investigation of aquaporin 1 (Aqp1) and sodium-potassium ATPase alpha 2 subunit (Atp1a2) expression.
• Examination of Sonic hedgehog (Shh) signaling pathways, including canonical and non-canonical routes.
• Ultrastructural analysis of choroid plexus cilia and their developmental changes.

Main Results:

• Defective ciliogenesis or intraflagellar transport in the choroid plexus leads to neonatal hydrocephalus, associated with increased Aqp1 and Atp1a2 expression.
• Choroid plexus multicilia function as sensory cilia, transducing both canonical and non-canonical Shh signaling.
• Non-canonical Shh signaling, mediated by Smo/Gαi/cAMP, represses Aqp1 and Atp1a2 expression.
• Unique ciliary ultrastructure and decreasing ciliary length during development lead to reduced Shh signaling, derepression of Aqp1/Atp1a2, and increased CSF production.

Conclusions:

• Developmental dynamics of choroid plexus multicilia play a key role in dampening Shh signaling intensity.
• This modulation of Shh signaling ultimately promotes cerebrospinal fluid production and prevents hydrocephalus.