Mammals are unique among vertebrates because they feed their young with specialized mammary glands. The ability to lactate is necessary for the survival of most non-human mammals and is highly desirable for the health and well-being of human infants. Approximately 40 percent of women in Western cultures have lactation defects that are extremely painful and often result in the cessation of breastfeeding. We have previously generated mice carrying a mutation in the winged helix transcription factor Mf3. Members of this gene family play important roles during embryonic development and postnatal homeostasis. The resulting lactation defect in the Mf3 -/- females is an ideal model to study general mechanisms of tissue differentiation, axonal circuitry and neural control. To determine the cellular basis of the Mf3 -/- defect we have insetted a lineage marker into the Mf3 locus to follow the fate of Mf3 expressing cells in the CNS and mammary glands. These experiments will test the following two hypotheses: Mf3 expression is necessary for proper axonal connections between the thalamus and hypothalamus, and Mf3 -/- females have defects in the axonal circuitry resulting in disruption of the milk-ejection reflex and Mf3 expression in the mammary glands is necessary for the normal development of mammary glands in utero and/or after puberty. Lactation is initiated by afferent stimuli of the young suckling at the nipple. This stimulus is transmitted via the spinal cord to the hypothalamus where oxytocin is released. Oxytocin acts on myoepithelial cells of the mammary gland causing them to contract and eject milk. Mf3 is expressed in restricted regions of the CNS and in developing mammary glands. Using the Cre-loxP system we will selectively mutate the Mf3 gene in the CNS to test the following hypothesis: The CNS expression of Mf3 is critical for the normal milk-ejection response. We will also delete Mf3 expression in mammary glands to test the following two hypotheses: 1. The ability to lactate normally is dependent on a functioning mammary gland and the embryonic expression of Mf3 is necessary for normal differentiation of the mammary gland. 2. The adult expression of Mf3 in the mammary gland is essential so the afferent suckling stimulus is transmitted via the spinal cord to the hypothalamus, oxytocin is released and milk is ejected. This model provides an important experimental paradigm to study general mechanisms of developmental regulation.
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