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WIREs Dev Biol
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Morphogenetic movements in the neural plate and neural tube: mouse

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The neural tube (NT), the embryonic precursor of the vertebrate brain and spinal cord, is generated by a complex and highly dynamic morphological process. In mammals, the initially flat neural plate bends and lifts bilaterally to generate the neural folds followed by fusion of the folds at the midline during the process of neural tube closure (NTC). Failures in any step of this process can lead to neural tube defects (NTDs), a common class of birth defects that occur in approximately 1 in 1000 live births. These severe birth abnormalities include spina bifida, a failure of closure at the spinal level; craniorachischisis, a failure of NTC along the entire body axis; and exencephaly, a failure of the cranial neural folds to close which leads to degeneration of the exposed brain tissue termed anencephaly. The mouse embryo presents excellent opportunities to explore the genetic basis of NTC in mammals; however, its in utero development has also presented great challenges in generating a deeper understanding of how gene function regulates the cell and tissue behaviors that drive this highly dynamic process. Recent technological advances are now allowing researchers to address these questions through visualization of NTC dynamics in the mouse embryo in real time, thus offering new insights into the morphogenesis of mammalian NTC. WIREs Dev Biol 2014, 3:59–68. doi: 10.1002/wdev.120 This article is categorized under: Early Embryonic Development > Gastrulation and Neurulation Nervous System Development > Vertebrates: Regional Development Birth Defects > Craniofacial and Nervous System Anomalies

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Morphological changes as the neural plate rolls up to form the neural tube (NT). (a) Thickening of the dorsal neuroepithelium results in formation of the neural plate. (b) The neuroepithelium bends dorsally to form the neural folds [medial hinge point (MHP) and dorsal‐lateral hinge point (DLHP)]. (c) Further bending brings the neural folds in close opposition to each other. Non‐neural ectoderm cells cover the edge of the neuroepithelium. (d) Separation of neural and non‐neural ectoderm and fusion of these tissues result in formation of the closed NT covered by a sheet of ectoderm. np, neural plate; E, epidermis or non‐neural ectoderm; m, mesoderm; nc, notochord.
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The Shroom3 mutation disrupts inflection and zipping progression, resulting in cranial neural tube defects (NTDs). All embryos are transgenic for VenMyr expressed constitutively in all embryonic tissues. Scale bars are 100 µm. a/p refer to anterior/posterior, respectively (see also Ref ). (a and b) Dorsal view of a wild‐type embryo (a) and a Shroom3 mutant embryo (b) at 13‐somite stage. Morphologically, Shroom3 mutants are different from wild‐type embryos, in that the open part of the NT is wider and longer than in wild‐type. (c and d) Dorsal view of a wild‐type embryo (c) and a Shroom3 mutant embryo (d) at 17‐somite stage. Morphologically, Shroom3 mutant embryos are severely abnormal. The neural folds in the mutant embryos are folded over themselves on each side of the brain region, and the open cranial neural folds are very irregular and misshapen, whereas in the wild‐type embryo the open neural folds are smooth and elliptically shaped.
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Cellular activity of the non‐neural ectoderm during zipping of the neural folds. Schematic of an embryo transgenic for Grhl3‐Cre and mTomato‐mGFP. The embryo expresses mTomato constitutively in all tissues except for non‐neural ectoderm adjacent to the neural folds in which Grhl3‐mediated Cre recombination has induced mGFP expression. White box indicates the region of the still images (right side) that highlight a variety of cell shapes including cellular bridges, filopodia, lamellipodia, and rosette formation. These still images are snapshots from Movie S5.
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Neural tube closure (NTC) in the mouse embryo. Schematic drawings of the initial points of NTC (green arrowheads) and zipping of the neural folds (light blue arrows) along the rostral‐caudal axis, and inflection of the neural folds (red arrows). The number in the right corners indicates the time in hours from live imaging experiments for the processes described in this figure. See also Ref . nf, neural folds. Closure point I: At the start of imaging of a 4‐ to 5‐somite embryo, the neural folds are elevated but they have not met at the dorsal midline. After 4 h, multiple contact points are formed between the opposed folds at the hindbrain/cervical boundary (green arrowheads). Zipping then takes place to close the neural folds both rostrally toward the head and caudally (light blue arrows). This process is shown in Movie S1. Closure point III: At the start of imaging of an 8‐somite embryo, the neural folds at the forebrain region are still far apart from each other. After 6 h of culture and imaging, closure point III is formed between the opposed folds at the most anterior part of the forebrain (green arrowheads), then zipping proceeds caudally toward the midbrain to close the neural folds (light blue arrow). Closure point II: At the start of imaging of a 14‐somite embryo, the neural folds at the forebrain region are closed by zipping proceeding from closure point III. After 2 h of culture and imaging, closure point II is formed between the opposed folds at the border between the posterior part of the forebrain and the anterior part of the midbrain (green arrowheads), then zipping proceeds rostrally along the forebrain (R) and caudally through the midbrain (C) to close the neural folds (light blue arrow). Anterior and hindbrain neuropore closure: At the start of imaging of a 17‐somite embryo, the forebrain region is closed but the neural folds remain open at the midbrain and hindbrain region. Inflection (red arrows) continues to bend the neural folds to bring them closer to each other, which allows zipping (light blue arrows) to effectively seal the NT along the dorsal midline. The right drawing shows the narrowing of the gap at the midbrain region. After 4 h of imaging the gap between the neural folds is much narrower and closure by zipping has significantly reduced the cranial region that remains open. This process is shown in Movie S2. Posterior neuropore (PNP) closure: At the start of imaging of an E10 embryo, the posterior neuropore remains open at the caudal part of the future spinal cord. Inflection (red arrows) of the opposed neural folds brings them closer to one another and zipping (light blue arrows) closes the NT along the dorsal midline. After 4 h of imaging, the gap between the PNP folds is narrowed.
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Morphogenetic processes promoting neural tube closure (NTC). Dynamic formation of dorsal‐lateral hinge points (DLHPs): schematic of optical cross sections of the midbrain region of a 15‐somite embryo from Movie S3. Apical constriction of the neural cells at the ventral midline forms the MHP and at the two dorsal‐lateral sides forms the DLHPs. DLHP formation leads to the bending of the opposed neural folds and brings the folds closer to one another (inflection). Live imaging shows that DLHP formation is dynamic rather than fixed in time and space. After 1 h of imaging, the folds relax, deforming the DLHPs, and later after 2.5 h, the DLHPs reform and closure proceeds. nf, neural folds; E, epidermis or non‐neural ectoderm; m, mesoderm; MHP, medial hinge point; DLHPs, dorsal‐lateral hinge points. Relationship between zipping and inflection: schematic drawings demonstrating the cutting experiments to test the relationship of zipping to inflection. A 13‐somite embryo was cut at two places (scissors) to separate the process of zipping from the regions undergoing inflection (midbrain/hindbrain). Inflection (red arrows) and zipping (light blue arrows) can continue independently. Inflection is sufficiently robust to bring the neural folds together to meet at the dorsal midline without the contribution of zipping. This indicates that inflection and zipping are two independent processes that facilitate NTC. However, the dynamics of each of these processes was affected, which suggests a disturbance of the balance of the forces generated by these two processes as a result of the physical cuts (see also Ref ). This experiment is shown in Movie S4.
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