Abstract
ABSTRACTGenetic variations affecting neural tube closure along the head result in malformations of the face and brain. Neural tube defects (NTDs) are among the most common birth defects in humans. We previously reported a mouse mutant called tuft that arose spontaneously in our wild-type 3H1 colony. Adult tuft mice present midline craniofacial malformations with or without an anterior cephalocele. In addition, affected embryos presented neural tube closure defects resulting in insufficient closure of the anterior neuropore or exencephaly. Here, through whole-genome sequencing, we identified a nonsense mutation in the Tet1 gene, which encodes a methylcytosine dioxygenase (TET1), co-segregating with the tuft phenotype. This mutation resulted in premature termination that disrupts the catalytic domain that is involved in the demethylation of cytosine. We detected a significant loss of TET enzyme activity in the heads of tuft embryos that were homozygous for the mutation and had NTDs. RNA-Seq transcriptome analysis indicated that multiple gene pathways associated with neural tube closure were dysregulated in tuft embryo heads. Among them, the expressions of Cecr2, Epha7 and Grhl2 were significantly reduced in some embryos presenting neural tube closure defects, whereas one or more components of the non-canonical WNT signaling pathway mediating planar cell polarity and convergent extension were affected in others. We further show that the recombinant mutant TET1 protein was capable of entering the nucleus and affected the expression of endogenous Grhl2 in IMCD-3 (inner medullary collecting duct) cells. These results indicate that TET1 is an epigenetic determinant for regulating genes that are crucial to closure of the anterior neural tube and its mutation has implications to craniofacial development, as presented by the tuft mouse.
Highlights
Neural tube defects (NTDs), such as anencephaly, encephalocele and spina bifida, are among the most common birth defects in humans, with estimates of over 2650 annual cases in the United States (Centers for Disease Control; www.cdc.gov)
The family of mice consisted of an affected male that exhibited craniofacial malformations with a cephalocele, which we previously described as a tuft trait (Fong et al, 2012), a normal-appearing female predicted to be a carrier for the tuft allele and three of their pups
Gene mutations associated with neural tube closure in humans are being identified, there is a need for understanding how environmental conditions influence their expression in order to address a broader spectrum of cases
Summary
Neural tube defects (NTDs), such as anencephaly, encephalocele and spina bifida, are among the most common birth defects in humans, with estimates of over 2650 annual cases in the United States (Centers for Disease Control; www.cdc.gov). Largely owing to prenatal supplementation of folic acid (FA) over the past 18 years in the United States (mandatory fortification authorized in 1996, but not fully implemented until 1998), NTDs remain among the most common serious birth defect. There are over 450 loci in mice documented in the Mouse Genome Informatics (MGI) database that are associated with neural tube closure defects. This underscores the complexity of neurulation and the different ways by which closure defects might arise.
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