Abstract
Neural tube closure defects are a major cause of infant mortality, with exencephaly accounting for nearly one-third of cases. However, the mechanisms of cranial neural tube closure are not well understood. Here, we show that this process involves a tissue-wide pattern of apical constriction controlled by Sonic hedgehog (Shh) signaling. Midline cells in the mouse midbrain neuroepithelium are flat with large apical surfaces, whereas lateral cells are taller and undergo synchronous apical constriction, driving neural fold elevation. Embryos lacking the Shh effector Gli2 fail to produce appropriate midline cell architecture, whereas embryos with expanded Shh signaling, including the IFT-A complex mutants Ift122 and Ttc21b and embryos expressing activated Smoothened, display apical constriction defects in lateral cells. Disruption of lateral, but not midline, cell remodeling results in exencephaly. These results reveal a morphogenetic program of patterned apical constriction governed by Shh signaling that generates structural changes in the developing mammalian brain.
Highlights
Neural tube closure defects are among the most common structural birth defects, occurring in 1 in 1000 pregnancies worldwide (Wallingford et al, 2013; Zaganjor et al, 2016)
The loss of Gli2, a transcriptional effector of Sonic hedgehog (Shh) signaling, disrupts cell architecture at the midline, whereas loss of the intraflagellar transport A (IFT-A) complex components Ift122 or Ttc21b disrupt apical constriction and actomyosin organization in lateral cells, resulting in a failure of cranial neural tube closure. These apical remodeling defects are recapitulated by activation of the Shh response throughout the midbrain, indicating that they are due to deregulated Shh signaling. These results demonstrate that lateral cells drive cranial neural tube closure through large-scale, coordinated apical constriction behaviors that are spatially regulated by patterned Shh activity
Neural tube closure defects are among the most common human birth defects, with one-third of cases arising from defects in closure of the cranial region (Zaganjor et al, 2016)
Summary
Neural tube closure defects are among the most common structural birth defects, occurring in 1 in 1000 pregnancies worldwide (Wallingford et al, 2013; Zaganjor et al, 2016). At later stages of closure, cells at the borders of the neural plate form dynamic protrusions and adhesions that join the left and right sides of the neural plate to produce a closed tube (Pyrgaki et al, 2010; Massarwa et al, 2014; Hashimoto et al, 2015; Ray and Niswander, 2016a; Ray and Niswander, 2016b; Moleet al., 2020) It is not known if localized forces at the midline and borders of the neural plate are sufficient for closure of the significantly larger cranial region, or if distinct cell populations and behaviors contribute to cranial neural structure. Results demonstrate that lateral cells drive cranial neural tube closure through large-scale, coordinated apical constriction behaviors that are spatially regulated by patterned Shh activity
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