Disease relevance of Exen1

• Using gene trap mutagenesis, we have identified a mutation in mice that causes exencephaly, acrania, facial clefting, and spina bifida, all of which can be attributed to failed neural tube closure [1].
• They exhibit multiple developmental defects, including failure of anterior neural tube closure (exencephaly), failure of digit septation (syndactyly), and dysmorphogenesis of the placental labyrinth [2].
• Twenty-five percent had exencephaly and 19% had omphalocele (normal frequencies, < 1%), indicating high frequencies of midline defects, particularly in cranial neurulation [3].
• In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones [4].
• The effects of this BP metabolite were very specific and malformations such as exencephaly, thoraco- and gastroschisis, phocomelia, and edema were found [5].

Psychiatry related information on Exen1

• Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (> or = 10,000 ppm) of methanol on gestational day 8 (GD8; copulation plug = GD0) [6].
• Treatment of pregnant dams (600 mg/kg sodium valproate in distilled water, i.p.) during the critical period on day 8 (D8) of gestation resulted in D14 exencephaly frequencies of 69% in SELH/Bc contrasted with 39% in each of the SWV/Bc and ICR/Bc strains [7].

High impact information on Exen1

• In addition, Brg1 heterozygotes are predisposed to exencephaly and tumors [8].
• The defects in the BM separating the brain from the adjacent mesenchyme caused invasion of brain tissue into the overlaying ectoderm leading to abnormal expansion of neuroepithelium, neuronal ectopias, and exencephaly [9].
• Targeted deletion of the Sp8 gene gives a striking phenotype, with severe truncation of both forelimbs and hindlimbs, absent tail, as well as defects in anterior and posterior neuropore closure leading to exencephaly and spina bifida [10].
• Hipk1 Hipk2 double homozygotes are progressively lost between 9.5 and 12.5 days postcoitus and frequently fail to close the anterior neuropore and exhibit exencephaly [11].
• Folic acid prevents exencephaly in Cited2 deficient mice [12].

Chemical compound and disease context of Exen1

• In the mouse, exogenous retinoic acid can induce both anterior (anencephaly, exencephaly) and posterior (spina bifida) neural tube defects depending on the developmental stage of treatment [13].
• With phenobarbital plus NNK, two fetuses had a cleft palate, two had exencephaly and one had a kinky tail, although phenobarbital controls showed no anomalies (P <.05) [14].
• Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA [15].
• Cadmium (Cd) administered to female C57BL/6 mice on gestation day 8 induces a high incidence of anterior neural tube defects (exencephaly) [16].
• Ethanol, however, increased VPA (400 mg/kg, SC)-induced exencephaly, embryolethality, and fetal weight retardation [17].

Biological context of Exen1

• The extremes, the 10 highest and 10 zero exencephaly-producing F(2) sires, were typed for 109 SSLP marker loci in a genome screen [18].
• Inheritance of either transgene resulted in perinatal lethality and multiple craniofacial malformations of varying severity, including mandibular hypoplasia, cleft secondary palate, exencephaly, and median facial cleft, which are among the severe craniofacial malformations observed in humans [19].
• The transcriptional modulator Cited2 is essential for embryonic development: Cited2-null embryos die during gestation with profound developmental abnormalities, including cardiac malformations, exencephaly and adrenal agenesis [20].
• The splotch (Sp) mouse mutant displays defects in neural crest cell migration and neural tube closure and serves as a model for the study of spina bifida, exencephaly, and Waardenburg syndrome type I in humans [21].
• These data provide evidence for the possible interaction of alcohol with the genetic susceptibility to exencephaly in this strain of mice [22].

Anatomical context of Exen1

• Exencephaly was seen in >10% of all embryos and resulted from a closure defect of the hindbrain [23].
• Estimation of alpha-fetoprotein in the amniotic fluid of fetuses of these mutants has shown that the levels are raised in fetuses with exencephaly and open spina bifida [24].
• They exhibit high frequencies of exencephaly, universal agenesis of forebrain commissures, and abnormalities of cerebral cortical and retinal lamination [25].
• Examples of developmental defects include cranioschisis, rachischisis, thoracoschisis, exencephaly, hamartomas, and anomalies of appendages, digestive, genital and urinary tracts, sense organs, limbs and girdles, tail and pharynx [26].
• RESULTS: A subset of animals heterozygous for the AP-2alpha mutation develop a midbrain exencephaly after the mutation was crossed for one generation in the 129/Ola mouse strain [27].

Associations of Exen1 with chemical compounds

• Like the female predominance of NTDs in humans, female Cd embryos were most likely to display exencephaly and were more responsive than males to the FA rescue [28].
• We examined whether Crooked tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs [28].
• Cadmium is a potent teratogen in laboratory animals, causing exencephaly when administered at early stages of development [29].
• Mapping a chromosomal locus for valproic acid-induced exencephaly in mice [30].
• Exencephaly and axial skeletal dysmorphogenesis induced by acute doses of ethanol in mouse fetuses [31].

Analytical, diagnostic and therapeutic context of Exen1

• When exposed to a high dose of sodium VPA (600 mg/kg) via maternal intraperitoneal injection on gestational day E8.5, the fetuses manifested exencephaly in a strain-dependent manner [30].
• Hyperthermia-induced exencephaly in mice: effect of multiple exposures [32].
• In the present study, mouse embryos from inbred strains known to differ in terms of their sensitivity to heat-induced exencephaly were treated in vivo and their heat shock response determined using SDS-PAGE electrophoretic techniques [33].
• Exencephaly was the only external malformation found in the control group [34].
• However, when pregnancy outcome was evaluated on Day 20, dose-dependent decreases in offspring survival and fetal weight were observed and the incidences of two malformations, microphthalmia and exencephaly, were increased [35].

References