Irene E. Zohn

The location of a point in a two-dimensional space can be defined by Cartesian coordinates that indicate its position relative to horizontal and vertical axes. This system was introduced in the 17^th century by René Descartes. While it helps find your place on a map, it also captures the journey of cells during embryonic development, particularly in the nervous system. There, gradients of chemical signals known as morphogens form the axes that shape the embryo along anterior-posterior, dorsal-ventral, and mediolateral planes (which run from head to tail, back to belly, and side-to-side). The position of a cell within these gradients will determine the set of genes it expresses and, therefore, its developmental fate and cell identity.

Neural tube defects (NTDs) are severe malformations of the central nervous system that arise from failure of neural tube closure. HECTD1 is an E3 ubiquitin ligase required for cranial neural tube closure in mouse models. NTDs in the Hectd1 mutant mouse model are due to the failure of cranial mesenchyme morphogenesis during neural fold elevation. Our earlier research has linked increased extracellular heat shock protein 90 (eHSP90) secretion to aberrant cranial mesenchyme morphogenesis in the Hectd1 model. Furthermore, overexpression of HECTD1 suppresses stress-induced eHSP90 secretion in cell lines. In this study, we report the identification of five rare HECTD1 missense sequence variants in NTD cases. The variants were found through targeted next-generation sequencing in a Chinese cohort of 352 NTD cases and 224 ethnically matched controls. We present data showing that HECTD1 is a highly conserved gene, extremely intolerant to loss-of-function mutations and missense changes. To evaluate the functional consequences of NTD-associated missense variants, functional assays in HEK293T cells were performed to examine protein expression and the ability of HECTD1 sequence variants to suppress eHSP90 secretion. One NTD-associated variant (A1084T) had significantly reduced expression in HEK293T cells. All five NTD-associated variants (p.M392V, p.T801I, p.I906V, p.A1084T, and p.P1835L) reduced regulation of eHSP90 secretion by HECTD1, while a putative benign variant (p.P2474L) did not. These findings are the first association of HECTD1 sequence variation with NTDs in humans.

Neural tube defects (NTDs) are severe malformations of the central nervous system that arise from failure of neural tube closure. HECTD1 is an E3 ubiquitin ligase required for cranial neural tube closure in mouse models. NTDs in the Hectd1 mutant mouse model are due to the failure of cranial mesenchyme morphogenesis during neural fold elevation. Our earlier research has linked increased secretion of extracellular heat shock protein 90 (eHSP90) to aberrant cranial mesenchyme morphogenesis in the Hectd1 model. Furthermore, overexpression of HECTD1 suppresses stress-induced eHSP90 secretion in cell lines. In this study, we report the identification of five rare HECTD1 missense sequence variants in NTD cases. The variants were found through targeted next-generation sequencing in a Chinese cohort of 352 NTD cases and 224 ethnically matched controls. We present data showing that HECTD1 is a highly conserved gene, extremely intolerant to loss-of-function mutations and missense changes. To evaluate the functional consequences of NTD-associated missense variants, functional assays in HEK293T cells were performed to examine protein expression and the ability of HECTD1 sequence variants to suppress eHSP90 secretion. One NTD-associated variant (A1084T) had significantly reduced expression in HEK293T cells. All five NTD-associated variants (p.M392V, p.T801I, p.I906V, p.A1084T, and p.P1835L) reduced regulation of eHSP90 secretion by HECTD1, while a putative benign variant (p.P2474L) did not. These findings are the first association of HECTD1 sequence variation with human disease and suggest that sequence variation in HECTD1 may play a role in the etiology of human NTDs.

Many studies support the link between parental obesity and the predisposition to develop adult-onset metabolic syndromes that include obesity, high blood pressure, dyslipidemia, insulin resistance, and diabetes in the offspring. As the prevalence of obesity increases in persons of childbearing age, so does metabolic syndrome in their descendants. Understanding how parental obesity alters metabolic programs in the progeny, predisposing them to adult-onset metabolic syndrome, is key to breaking this cycle. This review explores the basis for altered metabolism of offspring exposed to overnutrition by focusing on critical developmental processes influenced by parental obesity. We draw from human and animal model studies, highlighting the adaptations in metabolism that occur during normal pregnancy that become maladaptive with obesity. We describe essential phases of development impacted by parental obesity that contribute to long-term alterations in metabolism in the offspring. These encompass gamete formation, placentation, adipogenesis, pancreas development, and development of brain appetite control circuits. Parental obesity alters the developmental programming of these organs in part by inducing epigenetic changes with long-term consequences on metabolism. While exposure to parental obesity during any of these phases is sufficient to alter long-term metabolism, offspring often experience multiple exposures throughout their development. These insults accumulate to increase further the susceptibility of the offspring to the obesogenic environments of modern society.

Background Vitamin A regulates patterning of the pharyngeal arches, cranial nerves, and hindbrain that are essential for feeding and swallowing. In the LgDel mouse model of 22q11.2 deletion syndrome (22q11DS), morphogenesis of multiple structures involved in feeding and swallowing are dysmorphic. We asked whether changes in maternal dietary Vitamin A intake can modify cranial nerve, hindbrain and pharyngeal arch artery development in the embryo as well as lung pathology that can be a sign of aspiration dysphagia in LgDel pups. Methods Three defined amounts of vitamin A (4, 10, and 16 IU/g) were provided in the maternal diet. Cranial nerve, hindbrain and pharyngeal arch artery development was evaluated in embryos and inflammation in the lungs of pups to determine the impact of altering maternal diet on these phenotypes. Results Reduced maternal vitamin A intake improved whereas increased intake exacerbated lung inflammation in LgDel pups. These changes were accompanied by increased incidence and/or severity of pharyngeal arch artery and cranial nerve V (CN V) abnormalities in LgDel embryos as well as altered expression of Cyp26b1 in the hindbrain. Conclusions Our studies demonstrate that variations in maternal vitamin A intake can influence the incidence and severity of phenotypes in a mouse model 22q11.2 deletion syndrome.

During embryonic development, the central nervous system forms as the neural plate and then rolls into a tube in a complex morphogenetic process known as neurulation. Neural tube defects (NTDs) occur when neurulation fails and are among the most common structural birth defects in humans. The frequency of NTDs varies greatly anywhere from 0.5 to 10 in 1000 live births, depending on the genetic background of the population, as well as a variety of environmental factors. The prognosis varies depending on the size and placement of the lesion and ranges from death to severe or moderate disability, and some NTDs are asymptomatic. This chapter reviews how mouse models have contributed to the elucidation of the genetic, molecular, and cellular basis of neural tube closure, as well as to our understanding of the causes and prevention of this devastating birth defect.