Abstract
Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice.
Highlights
The mouse mammary gland is a powerful model system for the study of cellular differentiation and gene function in organ development at the molecular, cellular, organ and organismal levels [1, 2]
Disruption of Hoxd10 Leads to Impaired Lactation as a Single Gene Mutation, and this Effect Is Enhanced by Simultaneous Disruption of Hoxd9
To quantify the impact of the homozygous mutant phenotypes on pup survival, we examined homozygous, heterozygous, and wild type littermates from the ΔHoxd10 and ΔHoxd9/d10 lines for their ability to support litters through their first lactation as a measure of lactational fitness
Summary
The mouse mammary gland is a powerful model system for the study of cellular differentiation and gene function in organ development at the molecular, cellular, organ and organismal levels [1, 2]. Post-pubertal, and can be characterized as a series of morphological and functional transitions, or switches, in which critical developmental decisions are made concerning cell identity, cell fate, pattern formation, and differentiation [3,4,5]. These transitions are under both local and systemic control. Ductal development in the mammary gland begins during embryogenesis with the formation of a rudimentary ductal tree [6,7,8]. Upon reaching the limits of the fat pad, ductal elongation ceases and, unless stimulated by pregnancy, the ductal tree becomes relatively growth quiescent. While there is a small amount of milk protein synthesis in the virgin animal, the gland is neither morphologically nor functionally differentiated to secrete milk
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