Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions
Suifang Mao,
Rui Song,
Shibo Jin,
Song Pang,
Aleksandra Jovanovic,
Adam Zimmerman,
Peng Li,
Xinying Wu,
Michael F. Wendland,
Kerry Lin,
Wei-Chi Chen,
Semil P. Choksi,
Gang Chen,
Michael J. Holtzman,
Jeremy F. Reiter,
Ying Wan,
Zhenyu Xuan,
Yang K. Xiang,
C. Shan Xu,
Srigokul Upadhyayula,
Harald F. Hess,
Lin He
Affiliations
Suifang Mao
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Rui Song
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Shibo Jin
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Song Pang
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
Aleksandra Jovanovic
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Adam Zimmerman
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Peng Li
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Xinying Wu
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Michael F. Wendland
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Kerry Lin
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Wei-Chi Chen
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA
Semil P. Choksi
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
Gang Chen
Chongqing Key Laboratory of Cytomics, Chongqing 400038, China
Michael J. Holtzman
Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Jeremy F. Reiter
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
Ying Wan
Chongqing Key Laboratory of Cytomics, Chongqing 400038, China
Zhenyu Xuan
Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080, USA
Yang K. Xiang
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA; VA Northern California Health Care System, Mather, CA 95655, USA
C. Shan Xu
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
Srigokul Upadhyayula
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Corresponding author
Harald F. Hess
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Corresponding author
Lin He
Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Corresponding author
Summary: 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.
