| Popis: |
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. |
