An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure

Abstract

The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. These mutants identify genes needed for embryonic neural tube closure. Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff, 2007) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology. In addition to null mutations, some are hypomorphs or conditional mutants. Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs. Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease-activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants. Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism. The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial-caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology. Birth Defects Research (Part A) 88:653-669,

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

“…This knockout mouse is a fully penetrant folate-pathway mouse model that does not require feeding a folate-deficient diet to cause these phenotypes. More than 10 folate-related mouse mutants have been characterized thus far (16), but NTDs are observed in only three: Folr1, Shmt1, and Amt. Folr1 encodes folate receptor 1, one of the major folate transport systems, and homozygous knockout of Folr1 produces a severe folate deficiency in the embryo that can be rescued with maternal 5-formyl-THF supplementation (17).…”

Mechanisms of tissue fusion during development

“…There are over 240 mouse models of NTDs (Harris and Juriloff, 2010). Many are due to recessive mutations of individual genes, with some showing low penetrance NTDs when haploinsufficient.…”

DNA methylation analysis of Homeobox genes implicatesHOXB7hypomethylation as risk factor for neural tube defects

“…Cranial NTDs are mostly not compatible with life, while caudal NTDs give rise to lifelong disabilities. Although more than 250 genes are known to cause NTDs in mice 4,5 and many candidate genes have been studied in patient cohorts, the molecular basis underlying NTDs still remains largely unknown. Folic acid reduced the incidence of NTDs by 50-75%.…”