Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Liheng Wang, Yang Liu, George Stratigopoulos, Sunil Panigrahi, Lina Sui, Yiying Zhang, Charles A. Leduc, Hannah J. Glover, Maria Caterina De Rosa, Lisa C. Burnett, Damian J. Williams, Linshan Shang, Robin Goland, Stephen H. Tsang, Sharon Wardlaw, Dieter Egli, Deyou Zheng, Claudia A. Doege, Rudolph L. Leibel

Research output: Contribution to journalArticlepeer-review

Abstract

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.

Original languageEnglish (US)
Article numbere146287
JournalJournal of Clinical Investigation
Volume131
Issue number8
DOIs
StatePublished - Apr 15 2021

Bibliographical note

Funding Information:
We thank Haiqing Hua and Aiqun Li for discussions related to this work; Yao Li and Jing Yang for help with collecting the biopsy samples; Val Sheffield for BBSM390RKI mice; Kathryn Anderson for the anti-SMO antibody (Memorial Sloan Kettering, New York, New York, USA); Tamara Caspary for the anti-ARL13B antibody (Emory University, Atlanta, Georgia, USA); and Lianqun Yang of the Diabetes and Endocrinology Research Center Pathology Core at Columbia University for histological analysis. Some of the studies reported here were conducted in the Genomics and High Throughput Screening Shared Resource at Columbia University (NIH/NCI P30CA013696). This research was supported by NIH grant R01 DK52431-23, the New York Stem Cell Foundation, a NYSTEM IIRP awards (SDHDOH01-C32590GG-3450000 and C026184 to DE), the Rudin Foundation, the Russell Berrie Foundation Program in Cellular Therapies, the Diabetes (P30 DK63608-16) and Obesity Research (P30 DK26687-41) Center of Columbia University, R01DK093920, U54OD020351, R24EY028758, U01 EY030580, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437, New York State (N13G-275), and Foundation Fighting Blindness New York Regional Research Center Grants (PPA-1218-0751-COLU) 7T32DK00755925 and 1K01DK123199.

Funding Information:
We thank Haiqing Hua and Aiqun Li for discussions related to this work; Yao Li and Jing Yang for help with collecting the biopsy samples; Val Sheffield for BBSM390RKI mice; Kathryn Anderson for the anti-SMO antibody (Memorial Sloan Kettering, New York, New York, USA); Tamara Caspary for the anti-ARL13B antibody (Emory University, Atlanta, Georgia, USA); and Lianqun Yang of the Diabetes and Endocrinology Research Center Pathology Core at Columbia University for histological analysis. Some of the studies reported here were conducted in the Genomics and High Throughput Screening Shared Resource at Columbia University (NIH/NCI P30CA013696). This research was supported by NIH grant R01 DK52431-23, the New York Stem Cell Foundation, a NYSTEM IIRP awards (SDHDOH01-C32590GG-3450000 and C026184 to DE), the Rudin Foundation, the Russell Berrie Foundation Program in Cellular Therapies, the Diabetes (P30 DK63608-16) and Obesity Research (P30 DK26687-41) Center of Columbia University, R01DK093920, U54OD020351, R24EY028758, U01 EY030580, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437, New York State (N13G-275), and Foundation Fighting Blindness New York Regional Research Center Grants (PPA-1218-0751- COLU) 7T32DK00755925 and 1K01DK123199.

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

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