Ribonucleotide reductase subunit R1: a gene conferring sensitivity to valproic acid-induced neural tube defects in mice.
Neural tube defects (NTDs), although prevalent and easily diagnosed, are etiologically heterogeneous, rendering mechanistic interpretation problematic. To date, there is evidence that mammalian neural tube closure (NTC) initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to a region-specific NTDs, possibly arising through closure site-specific genetic mechanisms. Although recent efforts have focused on elucidating the genetic components of NTDs, a void persists regarding gene identification in closure site-specific neural tissue. To this end, experiments were conducted to identify neural tube closure site-specific genes that might confer regional sensitivity to teratogen-induced NTDs. Using an inbred mouse strain (SWV/Fnn) with a high susceptibility to VPA- induced NTDs that specifically targets and disrupts NTC between the prosencephalon and mesencephalon region (future fore/midbrain; neural tube closure site II), we identified a VPA-sensitive closure site II-specific clone. Sequencing of this clone from an SWV neural tube cDNA library confirmed that it encodes the r1 subunit of the cell cycle enzyme ribonucleotide reductase (RNR). The abundance of rnr-r1 mRNA was significantly increased in response to VPA drug treatment. This upregulated expression was accompanied by a significant decrease in cellular proliferation in the closure site II neural tube region of the embryos, as determined by ELISA cellular proliferation assays performed on BrdU-pulsed neuroepithelial cells in vivo. We hypothesize that rnr-r1 plays a critical role in the development of VPA-induced exencephaly.
Craig
J C
JC
Department of Veterinary Anatomy, Texas A & M University, College Station, Texas 77843-4458, USA.
Bennett
G D
GD
Miranda
R C
RC
Mackler
S A
SA
Finnell
R H
RH
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D005314:Embryonic and Fetal Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D015723:Gene Library; D020022:Genetic Predisposition to Disease; D051379:Mice; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000235:genetics*; D013723:Teratogens; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D012333:RNA, Messenger; D013723:Teratogens; D014635:Valproic Acid; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; C498690:Rrm1 protein, mouse