Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development
Open Access
- 7 February 2019
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 4 (3)
Abstract
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.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (dk52431-23)
- NYNORC (5P30DK02668)
- New York Stem Cell Foundation (n/a)
- May and Samuel Rudin Family Foundation (N/A)
- Russell Berrie Foundation Program in Cellular Therapy (n/a)
- Russell Berrie Foundation Neuroscience of Obesity Initiative (n/a)
- National Institute of Diabetes and Digestive and Kidney Diseases (F30DK108564)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK114008)
- Norges Idrettshøgskole (DK63608-12)
- Norges Idrettshøgskole (DK2668-33)
- Norges Idrettshøgskole (DK09512)
- MSCA-IF-2016 ARC-Neurohet (52319)
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