Does the cranial mesenchyme contribute to neural fold elevation during neurulation?

Abstract

The central nervous system is derived from the neural plate that undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a process known as neurulation. The cellular behaviors driving neurulation in the cranial region involve forces generated by the neural tissue itself as well as the surrounding epithelium and mesenchyme. Of interest, the cranial mesenchyme underlying the neural plate undergoes stereotypical rearrangements hypothesized to drive elevation of the neural folds. As the neural folds rise, the hyaluronate-rich extracellular matrix greatly expands resulting in increased space between individual cranial mesenchyme cells. Based on inhibitor studies, expansion of the extracellular matrix has been implicated in driving neural fold elevation; however, since the surrounding neural and epidermal ectoderm were also affected by inhibitor exposure, these studies are inconclusive. Similarly, treatment of neurulating embryos with teratogenic doses of retinoic acid results in altered organization of the cranial mesenchyme but alterations in surrounding tissues are also observed. The strongest evidence for a critical role for the cranial mesenchyme in neural fold elevation comes from studies of genes expressed exclusively in the cranial mesenchyme that when mutated result in exencephaly associated with abnormal organization of the cranial mesenchyme. Twist is the best studied of these and is expressed in both the paraxial mesoderm and neural crest derived cranial mesenchyme. Here we review the evidence implicating the cranial mesenchyme in providing a driving force for neural fold elevation to evaluate whether there is sufficient data to support this hypothesis.

Insights into the Etiology of Mammalian Neural Tube Closure Defects from Developmental, Genetic and Evolutionary Studies

“…The role of cranial mesenchyme (comprised of cranial mesoderm and neural crest cells after their emigration from the neuroectoderm) in the cranial neural tube has been studied in mouse, rat and chick embryos [ 117 ]. During cranial neural tube formation, the shape of the folds progresses from biconvex, with the mid-lateral folds cushioned on a large supporting cranial mesenchyme, to biconcave ( Figure 4 ).…”

“…The neural folds of the spinal region do not have the convex stage. During the process of cranial neural fold elevation, the mesenchyme expands by both increased numbers of cells and increased space between the cells [ 117 , 118 ] and this mesenchymal expansion and reorganization is thought to be important in causing elevation. During the biconvex stage, the neural crest cells leave the neuroectoderm of the lateral tips of the neural folds and begin to migrate subectodermally through the mesenchyme to the first branchial arch and facial prominence areas.…”

“…As the neural folds elevate, becoming biconcave, and the dorsolateral hinge points form, the mesodermal cells become more widely spaced in the medial region and more closely packed in the lateral region. The extracellular matrix undergoes changes in hyaluronic acid concentration that may provide a mechanism for elevation by mesenchyme expansion, as hydration of hyaluronic acid is known to cause expansion of mesenchyme [ 117 , 119 ].…”

“…Loss of function of the transcriptional regulator, Ski , [ 129 ] which causes exencephaly or split face [ 130 ], is sometimes listed as having abnormal cranial mesenchyme [ 117 ] but cranial tissues do not seem to have been studied during the period of cranial fold elevation [ 130 , 131 ], and an etiology of exencephaly based on effects on cranial mesenchyme seems unproven.…”

“…Mutations causing loss of function of the E3 ubiquitin ligase Hectd1 ( opm ) lead to midbrain exencephaly in all homozygotes and some heterozygotes [ 134 ]. Hectd1 is ubiquitously expressed in embryos, including the head mesenchyme, and the cause of exencephaly is attributable to the effects of Hectd1 deficiency on the cranial mesoderm cells, which are abnormally shaped and packed more densely than normal near the neural tube at the normal time of elevation, and which fail to orient parallel to the neuroepithelium [ 117 , 134 ]. The neural folds lack mesenchyme expansion and remain flat or convex and fail to form the dorsolateral hinge points.…”