Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development

Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural...

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Autores principales:	Sung-Eun Kim, Karla Robles-Lopez, Xuanye Cao, Kristyn Liu, Pooja J. Chothani, Nikitha Bhavani, Lauren Rahman, Saikat Mukhopadhyay, Bogdan J. Wlodarczyk, Richard H. Finnell
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Gpr161 midbrain craniofacial defects neural crest cells encephaloceles sonic hedgehog signaling Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ecc5e70a6a5042ecb24eddb2d625d9c3
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spelling	oai:doaj.org-article:ecc5e70a6a5042ecb24eddb2d625d9c32021-11-30T13:09:47ZWnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development1664-802110.3389/fgene.2021.761418https://doaj.org/article/ecc5e70a6a5042ecb24eddb2d625d9c32021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.761418/fullhttps://doaj.org/toc/1664-8021Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.Sung-Eun KimKarla Robles-LopezKarla Robles-LopezXuanye CaoKristyn LiuPooja J. ChothaniNikitha BhavaniLauren RahmanSaikat MukhopadhyayBogdan J. WlodarczykRichard H. FinnellRichard H. FinnellRichard H. FinnellFrontiers Media S.A.articleGpr161midbraincraniofacial defectsneural crest cellsencephalocelessonic hedgehog signalingGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gpr161 midbrain craniofacial defects neural crest cells encephaloceles sonic hedgehog signaling Genetics QH426-470
spellingShingle	Gpr161 midbrain craniofacial defects neural crest cells encephaloceles sonic hedgehog signaling Genetics QH426-470 Sung-Eun Kim Karla Robles-Lopez Karla Robles-Lopez Xuanye Cao Kristyn Liu Pooja J. Chothani Nikitha Bhavani Lauren Rahman Saikat Mukhopadhyay Bogdan J. Wlodarczyk Richard H. Finnell Richard H. Finnell Richard H. Finnell Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
description	Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.
format	article
author	Sung-Eun Kim Karla Robles-Lopez Karla Robles-Lopez Xuanye Cao Kristyn Liu Pooja J. Chothani Nikitha Bhavani Lauren Rahman Saikat Mukhopadhyay Bogdan J. Wlodarczyk Richard H. Finnell Richard H. Finnell Richard H. Finnell
author_facet	Sung-Eun Kim Karla Robles-Lopez Karla Robles-Lopez Xuanye Cao Kristyn Liu Pooja J. Chothani Nikitha Bhavani Lauren Rahman Saikat Mukhopadhyay Bogdan J. Wlodarczyk Richard H. Finnell Richard H. Finnell Richard H. Finnell
author_sort	Sung-Eun Kim
title	Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
title_short	Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
title_full	Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
title_fullStr	Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
title_full_unstemmed	Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
title_sort	wnt1 lineage specific deletion of gpr161 results in embryonic midbrain malformation and failure of craniofacial skeletal development
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/ecc5e70a6a5042ecb24eddb2d625d9c3
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Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development

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