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Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I

Hormones and Cancer Group, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Richard P. DiAugustine, National Institute of Environmental and Health Science, P.O. Box 12233, MD D4-04, Research Triangle Park, North Carolina 27709. E-mail: diaugus2{at}niehs.nih.gov.

Abstract

The development of the mouse mammary gland occurs postnatally. Hormonal activation of local growth factor pathways stimulates rapid elongation and branching of the rudimentary gland through the fatty stroma. Earlier studies showed that GH is required for mammary gland ductal morphogenesis and that IGF-I mediates this action of GH. In the present study we show that adult IGF-I^m/m mutant mice exhibit a marked reduction in levels of mammary gland and liver igf1 transcripts compared with controls. Whole mounts of the adult IGF-I^m/m mammary glands revealed ducts that extended to the limits of the fat pad; however, the number of bifurcation branch points in the ductal tree of the mutants was reduced by half compared with that of wild-type glands. In contrast, adult mutant mice with a liver-specific deletion of the igf1 gene obtained by Cre/loxP recombination strategy maintained the normal levels of mammary gland igf1 transcripts and did not exhibit a branching deficit in this organ. It was previously reported that this specific loss of liver IGF-I causes serum levels of IGF-I (endocrine) to decrease by approximately 75%, whereas the levels of tissue igf1 transcripts remain unchanged. On the basis of these findings, we propose that paracrine, not endocrine, IGF-I is important for mammary branching morphogenesis.