Association of embryonic inositol status with susceptibility to neural tube defects, metabolite profile, and maternal inositol intake.

Maternal nutrition contributes to gene-environment interactions that influence susceptibility to common congenital anomalies such as neural tube defects (NTDs). Supplemental myo-inositol (MI) can prevent NTDs in some mouse models and shows potential for prevention of human NTDs. We investigated effects of maternal MI intake on embryonic MI status and metabolism in curly tail mice, which are genetically predisposed to NTDs that are inositol-responsive but folic acid resistant.

AAV-mediated expression of mouse or human GLDC normalises metabolic biomarkers in a GLDC-deficient mouse model of Non-Ketotic Hyperglycinemia.

Non-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations in GLDC (glycine decarboxylase). Current treatments for NKH have limited effect and are not curative.

International Consensus Statement on the Radiological Evaluation of Dysraphic Malformations of the Spine and Spinal Cord.

Dysraphic malformations of the spine and spinal cord (DMSSC) represent a spectrum of common congenital anomalies typically (though not exclusively) affecting the lower spinal segments. These may be responsible for varying degrees of neurologic, orthopedic, and urologic morbidity. With advances in neuroimaging, it is now possible to better diagnose and evaluate these disorders both prenatally and postnatally.

Fecal-adherent mucus is a non-invasive source of primary human MUC2 for structural and functional characterization in health and disease.

The O-glycoprotein Mucin-2 (MUC2) forms the protective colon mucus layer. While animal models have demonstrated the importance of Muc2, few studies have explored human MUC2 in similar depth. Recent studies have revealed that secreted MUC2 is bound to human feces.

Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice.

Closed spinal dysraphisms are poorly understood malformations classified as neural tube (NT) defects. Several, including terminal myelocystocele, affect the distal spine. We have previously identified a NT closure-initiating point, Closure 5, in the distal spine of mice.

Morphological phenotyping after mouse whole embryo culture.

Morphological phenotyping of the mouse embryo is described at neurulation stages, primarily as a guide to evaluating the outcome of whole embryo cultures between embryonic days 8.5 and 9.5.

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model.

Background: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model.

Metabolic implications and safety of dolutegravir use in pregnancy.

Dolutegravir is recommended for all people living with HIV because of its efficacy, high barrier to resistance, favourable safety and tolerability profile, and affordability. Dolutegravir has the highest rates of viral suppression in pregnancy, therefore preventing perinatal HIV transmission. In view of these benefits, particularly for pregnant women, an important question is if dolutegravir is safe in pregnancy.

A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability.

The surface ectoderm exhibits spatially heterogenous tension that correlates with YAP localisation during spinal neural tube closure in mouse embryos.

The single cell layer of surface ectoderm (SE) which overlies the closing neural tube (NT) plays a crucial biomechanical role during mammalian NT closure (NTC), challenging previous assumptions that it is only passive to the force-generating neuroepithelium (NE). Failure of NTC leads to congenital malformations known as NT defects (NTDs), including spina bifida (SB) and anencephaly in the spine and brain respectively. In several mouse NTD models, SB is caused by misexpression of SE-specific genes and is associated with disrupted SE mechanics, including loss of rostrocaudal cell elongation believed to be important for successful closure.

Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse.

Understanding the molecular mechanisms that lead to birth defects is an important step towards improved primary prevention. Mouse embryos homozygous for the Kumba (Ku) mutant allele of Zic2 develop severe spina bifida with complete lack of dorsolateral hinge points (DLHPs) in the neuroepithelium. Bone morphogenetic protein (BMP) signalling is overactivated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos.

A topographical analysis of encephalocele locations: generation of a standardised atlas and cluster analysis.

Objective: Encephaloceles are considered to result from defects in the developing skull through which meninges, and potentially brain tissue, herniate. The pathological mechanism underlying this process is incompletely understood. We aimed to describe the location of encephaloceles through the generation of a group atlas to determine whether they occur at random sites or clusters within distinct anatomical regions.

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.

Background: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, whereas supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome, and congenital anomalies. Inositol status can be influenced by diet, synthesis, transport, utilization, and catabolism.

Live-Imaging Analysis of Epithelial Zippering During Mouse Neural Tube Closure.

Zippering is a phenomenon of tissue morphogenesis whereby fusion between opposing epithelia progresses unidirectionally over significant distances, similar to the travel of a zip fastener, to ultimately ensure closure of an opening. A comparable process can be observed during Drosophila dorsal closure and mammalian wound healing, while zippering is employed by numerous organs such as the optic fissure, palatal shelves, tracheoesophageal foregut, and presumptive genitalia to mediate tissue sealing during normal embryonic development. Particularly striking is zippering propagation during neural tube morphogenesis, where the fusion point travels extensively along the embryonic axis to ensure closure of the neural tube.

Synchronisation of apical constriction and cell cycle progression is a conserved behaviour of pseudostratified neuroepithelia informed by their tissue geometry.

Neuroepithelial cells balance tissue growth requirement with the morphogenetic imperative of closing the neural tube. They apically constrict to generate mechanical forces which elevate the neural folds, but are thought to apically dilate during mitosis. However, we previously reported that mitotic neuroepithelial cells in the mouse posterior neuropore have smaller apical surfaces than non-mitotic cells.

Two-Photon Cell and Tissue Level Laser Ablation Methods to Study Morphogenetic Biomechanics.

Laser ablation is routinely performed to infer mechanical tension in cells and tissues. Here we describe our method of two-photon laser ablation at the cellular and tissue level in mouse embryos. The primary outcome of these experiments is initial retraction following ablation, which correlates with, and so can be taken as a measure of, the tensile stress that structure was under before ablation.

Vangl2-environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension.

Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs.

Rescuing human fetal tissue research in the United States: A call for additional regulatory reform.

Research using human fetal tissue has saved millions of lives through vaccines and other advances, but was markedly restricted by federal regulations in 2019. Although the restrictions were partially reversed in 2021, additional regulatory changes are needed to prevent further damage to essential research programs while preserving protection for human subjects.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities.

Genetic interaction of Pax3 mutation and canonical Wnt signaling modulates neural tube defects and neural crest abnormalities.

Mouse models provide opportunities to investigate genetic interactions that cause or modify the frequency of neural tube defects (NTDs). Mutation of the PAX3 transcription factor prevents neural tube closure, leading to cranial and spinal NTDs whose frequency is responsive to folate status. Canonical Wnt signalling is implicated both in regulation of Pax3 expression and as a target of PAX3.