Cellular mechanisms underlying Pax3-related neural tube defects and their prevention by folic acid

Neural tube defects (NTDs), including spina bifida and anencephaly, are among the most common birth defects worldwide, but their underlying genetic and cellular causes are not well understood. Some NTDs are preventable by supplemental folic acid. However, despite widespread use of folic acid supplements and implementation of food fortification in many countries, the protective mechanism is unclear. Pax3 mutant (splotch; Sp2H) mice provide a model in which NTDs are preventable by folic acid and exacerbated by maternal folate deficiency. Here, we found that cell proliferation was diminished in the dorsal neuroepithelium of mutant embryos, corresponding to the region of abolished Pax3 function. This was accompanied by premature neuronal differentiation in the prospective midbrain. Contrary to previous reports, we did not find evidence that increased apoptosis could underlie failed neural tube closure in Pax3 mutant embryos, nor that inhibition of apoptosis could prevent NTDs. These findings suggest that Pax3 functions to maintain the neuroepithelium in a proliferative, undifferentiated state, allowing neurulation to proceed. NTDs in Pax3 mutants were not associated with abnormal abundance of specific folates and were not prevented by formate, a one-carbon donor to folate metabolism. Supplemental folic acid restored proliferation in the cranial neuroepithelium. This effect was mediated by enhanced progression of the cell cycle from S to G2 phase, specifically in the Pax3 mutant dorsal neuroepithelium. We propose that the cell-cycle-promoting effect of folic acid compensates for the loss of Pax3 and thereby prevents cranial NTDs

Vangl-dependent planar cell polarity signalling is not required for neural crest migration in mammals

The role of planar cell polarity (PCP) signalling in neural crest (NC) development is unclear. The PCP dependence of NC cell migration has been reported in Xenopus and zebrafish, but NC migration has not been studied in mammalian PCP mutants. Vangl2Lp/Lp mouse embryos lack PCP signalling and undergo almost complete failure of neural tube closure. Here we show, however, that NC specification, migration and derivative formation occur normally in Vangl2Lp/Lp embryos. The gene family member Vangl1 was not expressed in NC nor ectopically expressed in Vangl2Lp/Lp embryos, and doubly homozygous Vangl1/Vangl2 mutants exhibited normal NC migration. Acute downregulation of Vangl2 in the NC lineage did not prevent NC migration. In vitro, Vangl2Lp/Lp neural tube explants generated emigrating NC cells, as in wild type. Hence, PCP signalling is not essential for NC migration in mammals, in contrast to its essential role in neural tube closure. PCP mutations are thus unlikely to mediate NC-related birth defects in humans

Dynamic acetylation profile during mammalian neurulation

Neural tube defects (NTDs) result from failure of neural tube closure during embryogenesis. These severe birth defects of the central nervous system include anencephaly and spina bifida, and affect 0.5-2 per 1,000 pregnancies worldwide in humans. It has been demonstrated that acetylation plays a pivotal role during neural tube closure, as animal models for defective histone acetyltransferase proteins display NTDs. Acetylation represents an important component of the complex network of posttranslational regulatory interactions, suggesting a possible fundamental role during primary neurulation events. This study aimed to assess protein acetylation contribution to early patterning of the central nervous system both in human and murine specimens

Gene-environment interactions in the causation of neural tube defects : folate deficiency increases susceptibility conferred by loss of Pax3 function

Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp(2)(H)) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp(2)(H) embryos, demonstrating a gene-environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation

Use of high-frequency ultrasound to study the prenatal development of cranial neural tube defects and hydrocephalus in Gldc-deficient mice

Objective: We used non-invasive high-frequency ultrasound (HFUS) imaging to investigate embryonic brain development in a mouse model for neural tube defects (NTDs) and non-ketotic hyperglycinemia (NKH). Method: Using HFUS, we imaged embryos carrying loss of function alleles of Gldc encoding glycine decarboxylase, a component of the glycine cleavage system in mitochondrial folate metabolism, which is known to be associated with cranial NTDs and NKH in humans. We serially examined the same litter during the second half of embryonic development and quantified cerebral structures. Genotype was confirmed using PCR. Histology was used to confirm ultrasound findings. Results: High-frequency ultrasound allowed in utero detection of two major brain abnormalities in Gldc-deficient mouse embryos, cranial NTDs (exencephaly) and ventriculomegaly (corresponding with the previous finding of post-natal hydrocephalus). Serial ultrasound allowed individual embryos to be analysed at successive gestational time points. From embryonic day 16.5 to 18.5, the lateral ventricle volume reduced in wild-type and heterozygous embryos but increased in homozygous Gldc-deficient embryos. Conclusion: Exencephaly and ventriculomegaly were detectable by HFUS in homozygous Gldc-deficient mouse embryos indicating this to be an effective tool to study CNS development. Longitudinal analysis of the same embryo allowed the prenatal onset and progression of ventricle enlargement in Gldc-deficient mice to be determined

Ground-state and decay properties of neutron-rich Nb 106

The ground-state properties of neutron-rich Nb106 and its β decay into Mo106 have been studied using the CARIBU radioactive-ion-beam facility at Argonne National Laboratory. Niobium-106 ions were extracted from a Cf252 fission source and mass separated before being delivered as low-energy beams to the Canadian Penning Trap, as well as the X-Array and SATURN β-decay-spectroscopy station. The measured Nb106 ground-state mass excess of -66202.0(13) keV is consistent with a recent measurement but has three times better precision; this work also rules out the existence of a second long-lived, β-decaying state in Nb106 above 5 keV in excitation energy. The decay half-life of Nb106 was measured to be 1.097(21) s, which is 8% longer than the adopted value. The level scheme of the decay progeny, Mo106, has been expanded up to ≈4MeV. The distribution of decay strength and considerable population of excited states in Mo106 of J≥3 emphasizes the need to revise the adopted Jπ=1- ground-state spin-parity assignment of Nb106; it is more likely to be J≥3

Recent advances in β-decay spectroscopy at CARIBU

β-decay spectroscopy of nuclei far from stability can provide powerful insight into a broad variety of topics in nuclear science, ranging from exotic nuclear structure phenomena, stellar nucleosynthesis processes, and applied topics such as quantifying "decay heat" discrepancies for advanced nuclear fuel cycles. Neutronrich nuclei approaching the drip-line are difficult to access experimentally, leaving many key examples largely under studied. The CARIBU radioactive beam facility at Argonne National Laboratory exploits spontaneous fission of 252Cf in production of such beams. The X-Array and SATURN decay station have been commissioned to perform detailed decay spectroscopy of low-energy CARIBU beams. An extended science campaign was started during 2015; with projects investigating nuclear shape changes, collective octupole vibrations, β-delayed neutron emission, and decay-scheme properties which could explain the reactor antineutrino puzzle. In this article we review the current status of the setup, update on the first results and recent hardware upgrades, and look forward to future possibilities

γ -soft Ba 146 and the role of nonaxial shapes at N≈90

Low-spin states in the neutron-rich, N=90 nuclide Ba146 were populated following β decay of Cs146, with the goal of clarifying the development of deformation in barium isotopes through delineation of their nonyrast structures. Fission fragments of Cs146 were extracted from a 1.7-Ci Cf252 source and mass selected using the CAlifornium Rare Ion Breeder Upgrade (CARIBU) facility. Low-energy ions were deposited at the center of a box of thin β detectors, surrounded by a highly efficient high-purity Ge array. The new Ba146 decay scheme now contains 31 excited levels extending up to ∼2.5 MeV excitation energy, double what was previously known. These data are compared to predictions from the interacting boson approximation (IBA) model. It appears that the abrupt shape change found at N=90 in Sm and Gd is much more gradual in Ba and Ce, due to an enhanced role of the γ degree of freedom