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The ability to lactate is a process restricted to mammals and is necessary for the survival of nonhuman mammals. Female mice carrying a null mutation in the winged helix transcription factor Foxb1 (previously Mf3/Fkh5/TWH) have lactation defects on inbred genetic backgrounds. To determine the cellular basis of the Foxb1 lactation defect we have inserted a tau-lacZ lineage marker into the locus to follow the fate of Foxb1 expressing cells. This approach has revealed that Foxb1 is expressed in epithelial cells of developing and adult mammary glands as well as previously described regions of the central nervous system. Mammary glands from C57BL/6 Foxb1-/- mice have incomplete lobuloalveolar development. In addition, the tau-lacZ lineage label was used to determine that the mammillothalamic tract was lost in all Foxb1-/- mice. Finally, morphological defects in the inferior colliculi of the midbrain in Foxb1-/- mice correlate with the inability to lactate, suggesting that the midbrain defect, but not the loss of the mammillothalamic tract, may be responsible for the lactation defect.
Copyright 2001 Wiley-Liss, Inc.
The mouse Mf3 gene, also known as Fkh5 and HFH-e5.1, encodes a winged helix/forkhead transcription factor. In the early embryo, transcripts for Mf3 are restricted to the presomitic mesoderm and anterior neurectoderm and mesoderm. By 9.5 days post coitum, expression in the nervous system is predominantly in the diencephalon, midbrain and neural tube. After midgestation, the highest level of mRNA is in the mammillary bodies, the posterior-most part of the hypothalamus. Mice homozygous for a deletion of the mf3 locus on a [129 x Black Swiss] background display variable phenotypes consistent with a requirement for the gene at several stages of embryonic and postnatal development. Approximately six percent of the mf3-/- embryos show an open neural tube in the diencephalon and midbrain region, and another five percent show a severe reduction of the posterior body axis; both these classes of affected embryos die in utero. Surviving homozygotes have an apparently normal phenotype at birth. Postnatally, however, mf3-/- pups are severely growth retarded and approximately one third die before weaning. This growth defect is not a direct result of lack of circulating growth hormone or thyrotropin. Mice that survive to weaning are healthy, but they show an abnormal clasping of the hindfeet when suspended by the tail. Although much smaller than normal, the mice are fertile. However, mf3-/- females cannot eject their milk supply to feed their pups. This nursing defect can be corrected with interperitoneal injections of oxytocin. These results provide evidence that Mf3 is required for normal hypothalamus development and suggest that Mf3 may play a role in postnatal growth and lactation.