These OVE1799B-CA7B mice harbor a transposition-induced deletion of 273 kbp in mouse chromosome 18, including most of the coding sequences (exons 1-8) of Skor2 gene. These mice may be useful for studying cleft palate and cerebellar development.
Paul A Overbeek, Baylor College of Medicine
These OVE1799B-CA7B mice harbor a transposition-induced deletion of 273 kbp in mouse chromosome 18, including most of the coding sequence (exons 1-8) of the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene. The deletion spans a non-coding region upstream of the Skor2 start codon to Skor2 intron 8 [NCB137/mm9; 76,860,053-77,133,014]. Homozygous mice have complete absence of Skor2 transcript, with no expression from the Gal4-VP16-SV40 cassette. Homozygous mice have defects in cerebellar development (defective Purkinje cell development, severe reduction of granule cell proliferation, and malformation of the cerebellum). In addition, the donating investigator reports that most (~90%) homozygous mice exhibit complete clefting of the secondary palate. These homozygous mice die within 24-48 hours of birth resulting from failure to nurse, defective neuromuscular junction formation, and/or respiration failure. Less than 5% of homozygous mice exhibit patent palate. Homozygotes that survive are smaller than their siblings and show an unstable gait/ataxia throughout their life span.
A Sleeping Beauty (SB) transposon transgenic approach was used to generate these mice. The pT2-Tyro-Gal4-SV40 transposon vector used here has an inverted repeat/direct repeat sequence (IR/DR; the SB transposon recognition site [280 bp]), a Gal4-VP16-SV40pA sequence (1.7 kbp), the Tyro minigene (4.1 kbp), and right IR/DR (280 bp). The IR/DR sequences are outward-facing (pointed away from the Gal4-VP16-SV40pA::Tyro sequences). The Gal4-VP16-SV40 cassette is in the opposite orientation to the Tyro minigene. The 4.1 kb tyrosinase minigene (Tyro) was isolated from plasmid Ty811C and contains the tyrosinase upstream regulatory sequences (2.25 kb from the BALB/c tyrosinase promoter and the first 65 bp of exon 1) and a chimeric cDNA made with (from 5' to 3') the upstream part of the C57BL/6-derived Tyrs-J (cysteine at amino acid 103) sequence ligated at a central ScaI site to the downstream part of the DBA/2-derived tyrosinase (valine at amino acid 346).This transgene was microinjected into one-cell stage FVB/N embryos. Expression of the tyrosinase minigene results in melanin synthesis, and two founder mice (F0) were identified by inspection for pigmentation. F0 mice were assigned an OVE number and then bred with FVB/N mice. Pigmented offspring (F1) with different coat colors were designated as subline 1799A and 1799B. F1 mice were bred with FVB/N mice. F2 mice with identical coat colors were then inbred to generate homozygotes. Homozygous mice were viable and fertile. Homozygous mice were bred to mice with widespread expression of the SB transposase (CAGGS-SB10 transgenic mice on an FVB/N genetic background). The resulting double transgenic male offspring ("seed males") have the ability to mobilize transposons in their germline; and mobilization of the outward-facing, IR/DR site-flanked transposon results in transposon integration at new sites in the genome (as well as genomic rearrangements including deletions, inversions and translocations).Seed males were bred with FVB/N females, and offspring were screened for new coat colors (i.e.; new integration sites of the transposon). Mice with new transpositions (new F0 mice) were bred to FVB/N mice to establish new lines (CA1, CA2, etc.). F1 mice for each new line were inbred and assessed for the presence/absence of viable homozygotes. Hemizygous (and homozygous) mice of line OVE1799B-CA7B exhibit light grey mottle/medium brown coat color. The donating investigator reports the CAGGS-SB10 transgene was bred out of the line. Inverse PCR analysis identified that the transposition created a deletion of 273 kbp in mouse chromosome 18, including most of the coding sequences (exons 1-8) of the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene. The original integration site is a non-coding region 237 kbp upstream from the start codon of Skor2 [NCB137/mm9; 76,860,053]. The transposed integration site is intron 8 of Skor2 [NCB137/mm9; 77,133,014].Transgenic males were sent to The Jackson Laboratory Repository Facebase collection. Upon arrival, mice were bred to FVB/NJ inbred mice (Stock No. 001800) for at least one generation to establish the colony.
|Allele Name||transposon insertion 1799B.CA7B, Paul A Overbeek|
|Allele Type||Transposon induced|
|Gene Symbol and Name||Skor2, SKI family transcriptional corepressor 2|
|Gene Synonym(s)||CH18515; CORL2; Corl2; EG664805; FUSSEL18; Fussel18; Fussel18; Gm7348; Gm7348; Skor2-ps1; functional Smad suppressor element on chromosome 18; predicted gene 7348; predicted gene, EG664805|
|Strain of Origin||FVB/N|
|Molecular Note||Mobilization of TgTn(sb-Tyr)1799BOve with Sleeping Beauty transposase from Tg(CAG-sb10)1Dla results in the integrationof the transposon in a non-coding region 237 kbp upstream from the start codon of Skor2 [NCB137/mm9; 76,860,053] through intron 8 of Skor2 [NCB137/mm9; 77,133,014] deleting exons 1 through 8. Real-time RT-PCR confirmed the absence of transcript expression in the P0 cerebellum.|
|Mutations Made By|| |
Paul Overbeek, Baylor College of Medicine
Most homozygous mice die in the first 24-48 hours after birth with complications from cleft palate. When maintaining a live colony, heterozygous mice may be bred to wildtype siblings or to FVB/NJ inbred mice (Stock No. 001800).
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