title: Prenatal ablation of nicotinic receptor alpha7 cell lineages produces lumbosacral spina bifida the severity of which is modified by choline and nicotine exposure.
abstract: Lumbosacral spina bifida is a common debilitating birth defect whose multiple causes are poorly understood. Here, we provide the first genetic delineation of cholinergic nicotinic receptor alpha7 (Chrna7) expression and link the ablation of the Chrna7 cell lineage to this condition in the mouse. Using homologous recombination, an IRES-Cre bi-cistronic cassette was introduced into the 3' noncoding region of Chrna7 (Chrna7:Cre) for identifying cell lineages expressing this gene. This lineage first appears at embryonic day E9.0 in rhombomeres 3 and 5 of the neural tube and extends to cell subsets in most tissues by E14.5. Ablation of the Chrna7:Cre cell lineage in embryos from crosses with conditionally expressed attenuated diphtheria toxin results in precise developmental defects including omphalocele (89%) and open spina bifida (SB; 80%). We hypothesized that like humans, this defect would be modified by environmental compounds not only folic acid or choline but also nicotine. Prenatal chronic oral nicotine administration substantially worsened the defect to often include the rostral neural tube. In contrast, supplementation of the maternal diet with 2% choline decreased SB prevalence to 38% and dramatically reduced the defect severity. Folic acid supplementation only trended towards a reduced SB frequency. The omphalocele was unaffected by these interventions. These studies identify the Chrna7 cell lineage as participating in posterior neuropore closure and present a novel model of lower SB that can be substantially modified by the prenatal environment.
authors.affiliation: Salt Lake City VA Geriatric Research, Education and Clinical Center, Salt Lake City, Utah, USA. Scott.Rogers@hsc.utah.edu
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rogers
authors.forename: Petr
authors.initials: P
authors.lastname: Tvrdik
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.forename: Lorise C
authors.initials: LC
authors.lastname: Gahring
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002794:Choline / Q000494:pharmacology*; D005260:Female; D059765:Homologous Recombination; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000378:metabolism*; D016135:Spinal Dysraphism / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D002794:Choline