Abstract
During primary neurulation, the separation of a single-layered ectodermal sheet into the surface ectoderm (SE) and neural tube specifies SE and neural ectoderm (NE) cell fates. The mechanisms underlying fate specification in conjunction with neural tube closure are poorly understood. Here, by comparing expression profiles between SE and NE lineages, we observed that uncommitted progenitor cells, expressing stem cell markers, are present in the neural plate border/neural fold prior to neural tube closure. Our results also demonstrated that canonical Wnt and its antagonists, DKK1/KREMEN1, progressively specify these progenitors into SE or NE fates in accord with the progress of neural tube closure. Additionally, SE specification of the neural plate border via canonical Wnt signaling is directed by the grainyhead-like 3 (Grhl3) transcription factor. Thus, we propose that the fate specification of uncommitted progenitors in the neural plate border by canonical Wnt signaling and its downstream effector Grhl3 is crucial for neural tube closure. This study implicates that failure in critical genetic factors controlling fate specification of progenitor cells in the neural plate border/neural fold coordinated with neural tube closure may be potential causes of human neural tube defects.
Highlights
Neural tube defects are severe developmental disorders of the brain or spinal cord and one of the most common with a frequency of about 1 per 1000 births in humans (Mitchell, 2005)
Two additional stem cell markers, Klf5 transcripts and its proteins and SSEA-4, were expressed in the neural plate border (Fig. 1N–R, arrowheads). These findings indicate that a neural plate border region during neurulation possesses a stem cell-like character
Together with the above two lines of evidence that grainyhead-like 3 (Grhl3) expression in the neural plate border is regulated at the transcriptional level by the canonical Wnt signaling (Fig. 7A–G′) and that the defects in fate specification observed in the Dkk1-deficient embryos can be restored by the removal of Grhl3 gene dosage (Fig. 7I–L′′), these findings strongly suggested that Grhl3 and β-catenin genetically interact to achieve correct closure of the neural tube primarily in the fate specification of neural plate border cells
Summary
Neural tube defects are severe developmental disorders of the brain or spinal cord and one of the most common with a frequency of about 1 per 1000 births in humans (Mitchell, 2005). It is still unclear how genetic and environmental factors are associated with human neural tube defects. Little is known about what, when, and how molecular mechanisms control the fate specification decision between NE and SE cells in the neural plate border/neural fold, where these cells adjoin
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