ABSTRACT
The proximal albino deletions identify several functional regions on mouse Chromosome 7 critical for differentiation of mesoderm (mesd), development of the hypothalamus neuroendocrine lineage (nelg), and function of the liver (hsdr1). Using comparative mapping and genomic sequence analysis, we have identified four novel genes and Il16 in the mesd deletion interval. Two of the novel genes, mesdc1 and mesdc2, are located within the mesd critical region defined by BAC transgenic rescue. We have investigated the fetal role of genes located outside the mesd critical region using BAC transgenic complementation of the mesd early embryonic lethality. Using human radiation hybrid mapping and BAC contig construction, we have identified a conserved region of human chromosome 15 homologous to the mesd, nelg, and hsdr1 functional regions. Three human diseases cosegregate with microsatellite markers used in construction of the human BAC/YAC physical map, including autosomal dominant nocturnal frontal lobe epilepsy (ENFL2; also known as ADNFLE), a syndrome of mental retardation, spasticity, and tapetoretinal degeneration (MRST); and a pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA).
Subject(s)
Chromosomes, Human, Pair 15/genetics , Genes , Mesoderm/physiology , Sequence Analysis, DNA , Abnormalities, Multiple/genetics , Animals , Chromosomes, Artificial, Bacterial , Contig Mapping , Epilepsy, Frontal Lobe/genetics , Expressed Sequence Tags , Genetic Linkage , Humans , Mice , Microsatellite Repeats , Molecular Sequence Data , Mutation , Phenotype , Physical Chromosome Mapping , Radiation Hybrid Mapping , Sequence Deletion , SyndromeABSTRACT
The mesoderm development (mesd) functional interval is essential for primitive streak formation and mesoderm induction. Mesd is defined by overlapping albino (c) deletions on chromosome 7. We have constructed a bacterial artificial chromosome (BAC) contig that spans the mesd functional region. BAC end-sequence identifies three segments that recognize novel expressed sequences. Localization of the proximal breakpoints from Del(7)Tyr(c-3YPSd) and Del(7)Tyr(c-112K) within the contig defines a deletion interval of 310-350 kb that is essential for mesd function. Importantly, using BAC transgene rescue, we define a 75-kb mesd critical region containing at least one expressed sequence.
Subject(s)
Chromosome Mapping , Embryonic and Fetal Development/genetics , Mesoderm/physiology , Animals , Chromosomes, Artificial, Bacterial , Chromosomes, Artificial, Yeast , Gene Deletion , Genetic Markers , Mice , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , PhenotypeABSTRACT
The albino deletions identify at least seven functional intervals essential for pre- and postnatal development in the 6- to 10-cM region surrounding the albino coat color (c = tyrosinase) locus on mouse chromosome 7. The c112K deletion identifies a putative thymus functional region not removed by the overlapping c3H deletion. Cloning the c3H proximal breakpoint provided a starting point for construction of an 840-kb BAC contig spanning the c112K and c3H (D7Ssb3Hp) proximal breakpoints. These breakpoints are separated by 320-350 kb. The aryl hydrocarbon receptor nuclear translocator-2 (Arnt2) is completely removed by the c112K deletion and spans 130-170 kb of the interval. Although Arnt2 is a candidate for the thymus defects in c112K homozygotes, the possibility that other as yet unidentified genes in the c112K deletion are responsible for the abnormalities has not been ruled out. Arnt2 is a member of the bHLH-PAS (Per, Ahr, Arnt, Sim) family of transcription factors and shares the highest similarity with Arnt. The survival of c112K homozygotes markedly contrasts the embryonic lethality observed in Arnt-deficient embryos and suggests distinct roles for these related transcription factors during embryogenesis.
