Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9.

Area of Science:

• Developmental Biology
• Genetics
• Reproductive Biology

Background:

• The Hoxd10 gene plays a role in mammalian development.
• Mammary gland development and lactation are complex processes.
• The specific function of Hoxd10 in lactation has not been fully elucidated.

Purpose of the Study:

• To investigate the role of the Hoxd10 gene in mouse lactation.
• To determine the effect of combined Hoxd9 and Hoxd10 gene disruption on mammary function.
• To elucidate the molecular mechanisms underlying lactation impairment in Hoxd10 mutants.

Main Methods:

• Generation of homozygous Hoxd10 knockout (ΔHoxd10) and double knockout (ΔHoxd9/d10) mice.
• Comparative analysis of mammary gland morphology and function during pregnancy and lactation.
• Molecular analysis including protein expression (STAT5, STAT3, GLUT1), cell cycle, and apoptosis markers.
• Transplantation studies and hormone level analysis.

Main Results:

• Targeted disruption of Hoxd10 led to localized lactation impairment in 47% of homozygous mutant mice.
• Simultaneous disruption of Hoxd9 and Hoxd10 (ΔHoxd9/d10) resulted in complete lactation failure in 100% of females.
• Affected mammary glands showed reduced prolactin receptor and STAT5 signaling, altered GLUT1 localization, increased STAT3 signaling, inflammation, cell cycle changes, and apoptosis.
• Hoxd10 exhibits systemic functions affecting STAT5 phosphorylation in mammary gland transplants.

Conclusions:

• Hoxd10 is crucial for normal lactation, with its absence causing localized or complete milk production failure.
• The combined loss of Hoxd9 and Hoxd10 severely exacerbates lactation impairment.
• Hoxd10 influences mammary gland function systemically, impacting STAT5 signaling and contributing to lactation failure in C57Bl/6 mice.