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JCI Insight. 2019 Feb 7;4(3). pii: 123337. doi: 10.1172/jci.insight.123337. [Epub ahead of print]

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development.

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Naomi Berrie Diabetes Center and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.
Naomi Berrie Diabetes Center & Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Department of Biology, Indiana University-Purdue University, Indianapolis, Indiana, USA.
University of South Carolina School of Medicine, Columbia, South Carolina, USA.
University of Central Florida College of Medicine, Orlando, Florida, USA.
Institute of Human Nutrition graduate program, Columbia University, New York, New York, USA.
Zuckerman Institute, Columbia University, New York, New York, USA.
Cancer Research Laboratory Molecular Imaging Center, University of California, Berkeley, 94720, USA.
Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
National Center for Diabetes Research (DZD), Neuherberg, Germany.


Intronic polymorphisms in the α-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.


Embryonic development; Metabolism; NPY; Neuroscience; Obesity

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