Abstract
Failure of neural tube closure leads to neural tube defects (NTDs), common congenital abnormalities in humans. Among the genes whose loss of function causes NTDs in mice, Grainyhead-like3 (Grhl3) is essential for spinal neural tube closure, with null mutants exhibiting fully penetrant spina bifida. During spinal neurulation Grhl3 is initially expressed in the surface (non-neural) ectoderm, subsequently in the neuroepithelial component of the neural folds and at the node-streak border, and finally in the hindgut endoderm. Here, we show that endoderm-specific knockout of Grhl3 causes late-arising spinal NTDs, preceded by increased ventral curvature of the caudal region which was shown previously to suppress closure of the spinal neural folds. This finding supports the hypothesis that diminished Grhl3 expression in the hindgut is the cause of spinal NTDs in the curly tail, carrying a hypomorphic Grhl3 allele. Complete loss of Grhl3 function produces a more severe phenotype in which closure fails earlier in neurulation, before the stage of onset of expression in the hindgut of wild-type embryos. This implicates additional tissues and NTD mechanisms in Grhl3 null embryos. Conditional knockout of Grhl3 in the neural plate and node-streak border has minimal effect on closure, suggesting that abnormal function of surface ectoderm, where Grhl3 transcripts are first detected, is primarily responsible for early failure of spinal neurulation in Grhl3 null embryos.
Highlights
In higher vertebrates neural tube closure is achieved through coordinated shaping and bending of the neural plate to form bilateral neural folds which adhere in the midline (Greene and Copp, 2014; Nikolopoulou et al, 2017)
Genetic mapping and transgenic rescue provide evidence that the major genetic cause of neural tube defects (NTDs) in ct/ct embryos is a hypomorphic allele of Grhl3
It remained formally possible that reduced proliferation in the hindgut was a result of modifier gene action with NTDs resulting from summation with a deleterious effect of insufficient Grhl3 expression in another tissue
Summary
In higher vertebrates neural tube closure is achieved through coordinated shaping and bending of the neural plate to form bilateral neural folds which adhere in the midline (Greene and Copp, 2014; Nikolopoulou et al, 2017). Closure propagates between initial sites of adhesion to seal the intervening open regions, termed neuropores. Failure to complete closure results in severe birth defects, termed neural tube defects (NTDs), which include spina bifida and anencephaly (Copp et al, 2013). The leading edges of the neural folds at the closure site comprise neuroepithelium with overlying surface (non-neural) ectoderm and intervening extracellular matrix. Initial contact appears to be mediated by surface ectoderm cells at the boundary with the neuroepithelium at both cranial and spinal levels (Ray and Niswander, 2016; Rolo et al, 2016)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
