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ResearchIn-Press PreviewStem cells Free access | 10.1172/JCI146287

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

Liheng Wang,1 Yang Liu,2 George Stratigopoulos,3 Sunil K. Panigrahi,4 Lina Sui,4 Charles A. LeDuc,5 Hannah J. Glover,5 Maria Caterina De Rosa,4 Lisa C. Burnett,6 Damian J. Williams,7 Linshan Shang,8 Robin Goland,4 Stephen H. Tsang,9 Sharon L. Wardlaw,1 Dieter Egli,4 Deyou Zheng,2 Claudia A. Doege,4 and Rudolph L. Leibel3

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Wang, L. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Stratigopoulos, G. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Panigrahi, S. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Sui, L. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by LeDuc, C. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Glover, H. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by De Rosa, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

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1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Williams, D. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Shang, L. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Goland, R. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Tsang, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Wardlaw, S. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Egli, D. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Zheng, D. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Doege, C. in: JCI | PubMed | Google Scholar

1Department of Medicine, Columbia University, New York, United States of America

2Department of Genetics, Albert Einstein College of Medicine, New York, United States of America

3Department of Pediatrics, Columbia University, New York, United States of America

4Naomi Berrie Diabetes Center, Columbia University, New York, United States of America

5Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States of America

6Early Research and Development, Levo Therapeutics, Skokie, United States of America

7Institute for Genomic Medicine, Columbia University, New York, United States of America

8Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States of America

9Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Leibel, R. in: JCI | PubMed | Google Scholar

Published February 25, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI146287.
Copyright © 2021, American Society for Clinical Investigation
Published February 25, 2021 - Version history
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Abstract

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and 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 (iPSCs)-derived hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuron 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.

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