Is neural crest cell delamination required for normal cranial neural tube closure
2012
Numerous correlations are described in the literature between cranial neural tube defects
(NTDs) and neurocristopathies indicating that cranial neural tube closure and neural
crest cell (NCC) development may be linked by more than just spatial and temporal
contiguity. Detailed analysis of the morphology of the cranial neural plate identified the
midbrain as a region in which several features combine that are likely to result in
resistance to the apposition and subsequent closure of the neural folds. The relationship
between elevation, bending and closure of the midbrain neural folds and the
specification and delamination of NCC indicates that NCC may act in conjunction with
other permissive processes to facilitate a) elevation of the neural folds by contributing to
expansion of cranial mesenchyme and b) formation of dorsolateral hinge points (DLHP)
by reducing cell density and thus enhancing flexibility of the dorsal neural folds. These
two processes are requirements for the subsequent closure of the midbrain.
To address the hypothesis that NCC delamination is required for the elevation of
the midbrain neural folds and their bending at the DLHP, mouse models known to
harbour mutations resulting in both NTDs and neurocristopathies were studied to assess
the relationship between the two defects. In support of the idea that NCC delamination
facilitates midbrain elevation and DLHP formation, failure of cranial NCC delamination
associates with reduced cranial elevation, absence of DLHPs and midbrain exencephaly
in the Kumba mutant mouse model. This is in contrast to the dissociation between the
trunk NCC phenotype and hindbrain exencephaly observed in the Splotch model. The
hypothesis was tested experimentally by chemically inhibiting the delamination of NCC
in cultured embryos. This adversely affected elevation of the neural folds and DLHP
formation, and in some instances resulted in failure of midbrain closure. A transgenic
model was developed which was predicted to provide an in vivo model of inhibition of
delamination of NCC. The shRNA mediated knockdown of FoxD3 expression in NCC
did not, however, affect the early specification or delamination of NCC. Instead it
resulted in a failure of maintenance of NCC progenitors during their migration in the
cranial mesenchyme. This model displayed no incidence of midbrain exencephaly.
Failure of proper NCC derived mesenchymal ‘scaffolding’ surrounding the cranial
neural tube did, however, lead to a reopening of the forebrain in some instances.
Based on the evidence described above, I propose a model in which the
development of NCC exerts complex multilevel mechanical regulation on the formation
and maintenance of the neural tube. NCC delamination facilitates DLHP formation,
while NCC migration and proliferation in the mesenchyme contributes to elevation of
the cranial neural folds and also ‘scaffolds’ the neural folds to maintain closure.
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