Search

Hectd1 mutant mouse embryos exhibit the neural tube defect exencephaly associated with abnormal cranial mesenchyme. Cellular rearrangements in cranial mesenchyme are essential during neurulation for elevation of the neural folds. Here we investigate the molecular basis of the abnormal behavior of Hectd1 mutant cranial mesenchyme. We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Extracellular Hsp90 enhances migration of multiple cell types. In mutant cranial mesenchyme cells, both secretion of Hsp90 and emigration of cells from cranial mesenchyme explants were enhanced. Importantly, we show that this enhanced emigration was highly dependent on the excess Hsp90 secreted from mutant cells. Together, our data set forth a model whereby increased secretion of Hsp90 in the cranial mesenchyme of Hectd1 mutants is responsible, at least in part, for the altered organization and behavior of these cells and provides a potential molecular mechanism underlying the neural tube defect.

Neural tube defects (NTDs) represent some of the most common congenital malformations in humans. The causes of NTDs are complex with both genetic and environmental contributing factors. Periconception nutrition is an important environmental factor influencing the penetrance of NTDs. NTDs arise from failure to close the neural tube completely during development, an event that occurs before establishment of the chorioallantoic placenta. During neurulation, nutrients are absorbed by histotrophic mechanisms and absorbed by endocytosis in the endoderm-derived cell layer of the visceral yolk sac (VYS). Here we review the histotrophic mechanisms by which nutrients are delivered to the human embryo during this critical time period. Because more detailed studies on the molecular mechanisms regulating uptake of nutrients have been performed using rodent models, most importantly mouse and rat models, we will also review nutrient uptake in these model organisms to set the stage for presentation of experimental data that have provided valuable information about how nutrients are delivered to the neurulating embryo.

Neural tube defects (NTDs) are among the most common structural birth defects observed in humans. Mouse models provide an excellent experimental system to study the underlying causes of NTDs. These models not only allow for identification of the genes required for neurulation, they provide tractable systems for uncovering the developmental, pathological and molecular mechanisms underlying NTDs. In addition, mouse models are essential for elucidating the mechanisms of gene-environment and gene-gene interactions that contribute to the multifactorial inheritance of NTDs. In some cases these studies have led to development of approaches to prevent NTDs and provide an understanding of the underlying molecular mechanism of these therapies prevent NTDs.