Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions
The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by the Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in the developing choroid plexus, a derepression of Aqp1 and Atp1a2, and, ultimately, increased CSF production. Hence, the developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.
Authors
- Shibo Jin (ORCID: https://orcid.org/0000-0003-3514-4605)
- Kaili Lin (ORCID: https://orcid.org/0000-0002-1900-9641)
- C. Shan Xu (ORCID: https://orcid.org/0000-0002-8564-7836)
- Srigokul Upadhyayula (ORCID: https://orcid.org/0000-0001-6727-5883)
- Ying Wan (ORCID: https://orcid.org/0000-0001-7922-4434)
- Zhenyu Xuan (ORCID: https://orcid.org/0000-0001-9344-8493)
- Michael J. Holtzman (ORCID: https://orcid.org/0000-0001-8750-3716)
- Suifang Mao
- Song Pang (ORCID: https://orcid.org/0000-0002-7231-4151)
- Semil P. Choksi (ORCID: https://orcid.org/0000-0002-9319-7230)
- Wei-Chi Chen
- Jeremy F. Reiter (ORCID: https://orcid.org/0000-0002-6512-320X)
- Harald F. Hess (ORCID: https://orcid.org/0000-0003-3000-1533)
- Lin He (ORCID: https://orcid.org/0000-0001-5928-1263)
- Rui Song (ORCID: https://orcid.org/0000-0003-1875-2115)
- Gang Chen (ORCID: https://orcid.org/0000-0002-8105-2384)
- Peng Li (ORCID: https://orcid.org/0000-0002-5078-5091)
- Xinying Wu (ORCID: https://orcid.org/0000-0003-3808-5559)
- Yang Xiang (ORCID: https://orcid.org/0000-0001-7920-7554)
- Aleksandra Jovanović (ORCID: https://orcid.org/0000-0001-8809-8951)
- Michael F. Wendland
- A.M. Zimmerman
Institutions
- Howard Hughes Medical Institute (US)
- Chongqing University (CN)
- The University of Texas at Dallas (US)
- University of California, San Francisco (US)
- Janelia Research Campus (US)
- Washington University in St. Louis (US)
- Yale University (US)
- Chan Zuckerberg Initiative (United States) (US)
- VA Northern California Health Care System (US)
- University of California, Davis (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115383
- Citations
- 6
- Primary Topic
- Hedgehog Signaling Pathway Studies
- Type
- article
- Field-Weighted Citation Impact
- 4.84