Universität zu Köln

Wang, Liheng, De Solis, Alain J., Gaffer, Yossef, Birkenbach, Kathryn E., Engle, Staci E., Tanis, Ross, Levenson, Jacob M., Li, Xueting, Rausch, Richard, Purohit, Manika, Lee, Jen-Yi, De Rosa, Maria Caterina, Doege, Claudia A., Aaron, Holly L., Martins, Gabriela J., Bruening, Jens C., Egli, Dieter, Costa, Rui, Berbari, Nicolas, Leibel, Rudolph L. and Stratigopoulos, George ORCID: 0000-0003-4752-9123 (2019). Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development. JCI Insight, 4 (3). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

Intronic polymorphisms in the a-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Liheng UNSPECIFIED UNSPECIFIED UNSPECIFIED De Solis, Alain J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaffer, Yossef UNSPECIFIED UNSPECIFIED UNSPECIFIED Birkenbach, Kathryn E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Engle, Staci E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tanis, Ross UNSPECIFIED UNSPECIFIED UNSPECIFIED Levenson, Jacob M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Xueting UNSPECIFIED UNSPECIFIED UNSPECIFIED Rausch, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Purohit, Manika UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Jen-Yi UNSPECIFIED UNSPECIFIED UNSPECIFIED De Rosa, Maria Caterina UNSPECIFIED UNSPECIFIED UNSPECIFIED Doege, Claudia A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aaron, Holly L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martins, Gabriela J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Egli, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Costa, Rui UNSPECIFIED UNSPECIFIED UNSPECIFIED Berbari, Nicolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Leibel, Rudolph L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stratigopoulos, George UNSPECIFIED orcid.org/0000-0003-4752-9123 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-156858
DOI:	10.1172/jci.insight.123337
Journal or Publication Title:	JCI Insight
Volume:	4
Number:	3
Date:	2019
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	2379-3708
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; BASAL BODY PROTEIN; FTO GENE; JOUBERT SYNDROME; TRANSITION ZONE; ENERGY-INTAKE; FOOD-INTAKE; OBESITY; EXPRESSION; VARIANTS Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15685