Male-to-female sex reversal in M33 mutant mice

Abstract

Polycomb genes in Drosophila maintain the repressed state of homeotic and other developmentally regulated genes by mediating changes in higher-order chromatin structure. M33, a mouse homologue of Polycomb, was isolated by means of the structural similarity of its chromodomain. The fifth exon of M33 contains a region of homology shared by Drosophila and Xenopus. In Drosophila, its deletion results in the loss of Polycomb function. Here we have disrupted M33 in mice by inserting a poly(A) capture-type neo(r) targeting vector into its fifth exon. More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal. Formation of genital ridges was retarded in both XX and XY M33cterm/M33cterm embryos. Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry. M33cterm/M33cterm mice may be a valuable model in which to test opposing views regarding sex determination.

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

“…As reported previously, mice deficient in bmi1 (van der Lugt et al, 1994), mel18 (Akasaka et al, 1996), M33 (Córe et al, 1997;Katoh-Fukui et al, 1998), rae28 (Takihara and Hara, 2000), and ring1A (del Mar Lorente et al, 2000) revealed transformations along the anteroposterior (A-P) axis, similar to PcG mutations in flies, which are presumed to be caused by the altered expression of Hox genes. In addition, mutations in eed were also found to lead to impaired A-P patterning at an earlier stage (Schumacher et al, 1996).…”

The Y chromosome of the Okinawa spiny rat, Tokudaia muenninki, was rescued through fusion with an autosome

“…The Cbx2/CBX2 gene is a single copy gene in mice and humans and is known be involved in gonadal differentiation. The knockout of Cbx2 in mouse causes male-to-female sex reversal, and that mouse with the karyotype 40, XY has normal female external genitalia, which indicates that Cbx2/CBX2 represses ovarian development (Katoh-Fukui et al 1998;Biason-Lauber et al 2009). CBX2 occurs at two loci in T. osimensis and T. tokunoshimensis, owing to the translocation of a duplicated copy of the gene to another autosome.…”

Candidate testis‐determining gene, Maestro (Mro), encodes a novel HEAT repeat protein

“…In addition to SRY and SOX9, a survey of other key genes functioning during sex determination, such as WNT4 (Vainio et al, 1999), DAX1 (Swain et al, , 1998, WT1 (Pelletier et al, 1991), DMRT1 (Raymond et al, 1999(Raymond et al, , 2000, SF1 (Sadovsky et al, 1995;Ikeda et al, 1996), AMH (Mü nsterberg and Behringer et al, 1994), DHH (Bitgood et al, 1996), M33 (Katoh-Fukui et al, 1998), and FGF9 (Colvin et al, 2001), reveals that transcriptional regula-tors are represented at unusually high frequency. The putative missing genes from this pathway, such as those encoding additional membrane-bound or secreted signaling molecules, their receptors, signal transduction elements, protein trafficking mediators, nuclear import/ export regulators, growth factors, enzymes, and structural proteins remain to be identified.…”