Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification

The mouse scaramanga (ska) mutation impairs mammary gland development such that both abrogation and stimulation of gland formation occurs. We used positional cloning to narrow the interval containing scaramanga (ska) to a 75.6-kb interval containing the distal part of the Neuregulin3 (Nrg3) gene. Wi...

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Bibliographic Details
Published in:Genes & development 2005-09, Vol.19 (17), p.2078-2090
Main Authors: Howard, Beatrice, Panchal, Heena, McCarthy, Afshan, Ashworth, Alan
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Choristoma - genetics
Choristoma - metabolism
Cloning, Molecular
DNA, Complementary - genetics
ErbB Receptors - genetics
Female
Gene Expression Profiling
Gene Expression Regulation, Developmental
Genes, erbB-2
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Mammary Glands, Animal - embryology
Mammary Glands, Animal - metabolism
Mesoderm - cytology
Mesoderm - metabolism
Mice
Mice, Inbred A
Mice, Mutant Strains
Mutation
Neuregulins
Physical Chromosome Mapping
Receptor, ErbB-4
Research Papers
Signal Transduction
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Summary:The mouse scaramanga (ska) mutation impairs mammary gland development such that both abrogation and stimulation of gland formation occurs. We used positional cloning to narrow the interval containing scaramanga (ska) to a 75.6-kb interval containing the distal part of the Neuregulin3 (Nrg3) gene. Within this region the only sequence difference between ska and wild-type mice is in a microsatellite repeat within intron 7. This alteration correlates with variations in Nrg3 expression profiles both at the whole embryo level and locally in the presumptive mammary region in ska mice. Localized expression of Nrg3 and its receptor, Erbb4, in the presumptive mammary region around the future bud site prior to morphological appearance of buds and the expression of bud epithelial markers further support an inductive role. Finally, Neuregulin3 (Nrg3)-soaked beads can induce expression of the early bud marker Lef1 in mouse embryo explant cultures, and epithelial bud formation can be observed histologically, suggesting that initiation of mammary bud development occurs. Taken together, these results indicate that a Neuregulin signaling pathway is involved in specification of mammary gland morphogenesis and support the long-held view that mesenchymal signal(s) are responsible for mammary gland inductive/initiating events.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.338505