A novel mutation, repro5, was isolated in a forward genetic screen for infertility mutations induced by ENU mutagenesis. Homozygous mutant mice were phenotypically normal but were infertile. Oocytes f Show more
A novel mutation, repro5, was isolated in a forward genetic screen for infertility mutations induced by ENU mutagenesis. Homozygous mutant mice were phenotypically normal but were infertile. Oocytes from mutant females appeared normal, but were severely maturation-defective in that they had reduced ability to progress to metaphase II (MII), and those reaching MII were unable to progress beyond the two pronuclei stage following in vitro fertilization (IVF). Mutant males exhibited defective spermiogenesis, resulting in oligoasthenoteratospermia. Genetic mapping, positional cloning, and complementation studies with a disruption allele led to the identification of a mutation in Brwd1 (Bromodomain and WD repeat domain containing 1) as the causative lesion. Bromodomain-containing proteins typically interact with regions of chromatin containing histones hyperacetylated at lysine residues, a characteristic of chromatin in early spermiogenesis before eventual replacement of histones by the protamines. Previous data indicated that Brwd1 is broadly expressed, encoding a putative transcriptional regulator that is believed to act on chromatin through interactions with the Brg1-dependent SWI/SNF chromatin-remodeling pathway. Brwd1 represents one of a small number of genes whose elimination disrupts gametogenesis in both sexes after the major events of meiotic prophase I have been completed. Show less
The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling. Although mammalian genomes contain only three neurexin genes, thousan Show more
The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling. Although mammalian genomes contain only three neurexin genes, thousands of neurexin isoforms may be expressed through the use of two alternative promoters and alternative splicing at up to five different positions in the pre-mRNA. To begin understanding how the expression of the neurexin genes is regulated, we have determined the complete nucleotide sequence of all three human neurexin genes: NRXN1, NRXN2, and NRXN3. Unexpectedly, two of these, NRXN1 ( approximately 1.1 Mb) and NRXN3 ( approximately 1.7 Mb), are among the largest known human genes. In addition, we have identified several conserved intronic sequence elements that may participate in the regulation of alternative splicing. The sequences of these genes provide insight into the mechanisms used to generate the diversity of neurexin protein isoforms and raise several interesting questions regarding the expression mechanism of large genes. Show less