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A New Role of Ronin (Thap11) in the Neural Crest and Craniofacial Development in the Mouse
Author(s) -
Achilleos Annita,
Tong Xuefei,
Poché Ross A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.387.2
Subject(s) - neural crest , sox2 , biology , homeobox protein nanog , craniofacial , microbiology and biotechnology , embryonic stem cell , cre recombinase , population , pax6 , transcription factor , genetics , induced pluripotent stem cell , embryo , genetically modified mouse , transgene , gene , demography , sociology
The neural crest (NC) is a transient, multipotent, migratory cell population that is a hallmark of vertebrate evolution and gives rise to a diverse array of tissue types including sensory neurons and craniofacial skeleton. Development of the NC is a multistep process involving specification, epithelial to mesenchymal transition, migration and differentiation. Although a gene regulatory network that includes numerous transcription factors governing various stages of NC differentiation has been revealed over the last twenty years, a great deal is yet to be revealed regarding the factors essential for the lineage's multi‐potential nature in mammals. Ronin (Thap11) is a transcriptional regulator previously shown to be essential for maintaining the pluripotency of embryonic stem cells independently of the known pluripotency factors Sox2, Oct4 , and Nanog . We therefore sought to investigate whether Ronin may play a role in maintaining the multipotency of the NC in a similar fashion. Here we report for the first time a conditional knock‐out of Ronin in the NC using the Cre recombinase driven by the Wnt1 promoter (termed Wnt1‐Cre +/tg ;Ronin flx/flx ) in the mouse. Remarkably, Wnt1‐Cre +/tg ;Ronin flx/flx mouse embryos exhibit very severe craniofacial defects with almost all of the NC‐derived craniofacial skeleton missing. Interestingly, knock‐out of Ronin in a subset of the NC using the Pdgfrα‐Cre (Pdgfrα‐Cre +/tg ;Ronin flx/flx ) shows a different and very unique phenotype. Pdgfrα‐Cre +/tg ;Ronin flx/flx mice are born and maintain a grossly normal phenotype at birth, but fail to ossify a large portion of their calvaria. To our surprise these mice, despite the extensive calvarial phenotype, do well in terms of early development indicating grossly normal brain function. Interestingly, this phenotype is reminiscent of a rare congenital disorder called acalvaria, regarding which the causative gene(s) and pathophysiology are still unknown. Moreover, Ronin has been implicated in a rare cobalamin‐deficiency disorder (termed cblX). Consistent with our findings, these patients present with craniofacial abnormalities. This is the first study to reveal a role of Ronin in the NC and craniofacial development and continued investigation using these recently generated Ronin conditional knock‐out models will be crucial in revealing the pathophysiology of the described rare birth defects as well as furthering our understanding of the mechanisms underlying the extensive multipotent developmental plasticity of the neural crest.