The Gli2 transcription factor is required for normal mouse mammary gland development

The hedgehog signal transduction network performs critical roles in mediati ng cell-cell interactions during embryogenesis and organogenesis. Loss-of-f unction or misexpression mutation of hedgehog network components can cause birth defects, skin cancer, and other tumors. The Gli gene family (Gli1, Gl i2, and Gli3) encodes zinc finger transcription factors that act as mediato rs of hedgehog signal transduction. In this study, we investigate the role of Gli2 in mammary gland development. Mammary expression of Gli2 is develop mentally regulated in a tissue compartment-specific manner. Expression is e xclusively stromal during virgin stages of development but becomes both epi thelial and stromal during pregnancy and lactation. The null phenotype with respect to both ductal and alveolar development was examined by transplant ation rescue of embryonic mammary glands into physiologically normal host f emales. Glands derived from both wild type and null embryo donors showed du ctal outgrowths that developed to equivalent extents in virgin hosts. Howev er, in null transplants, ducts were frequently distended or irregularly sha ped and showed a range of histological alterations similar to micropapillar y ductal hyperplasias in the human breast. Alveolar development during preg nancy was not overtly affected by loss of Gli2 function. Ductal defects wer e not observed when homozygous null epithelium was transplanted into a wild type stromal background, indicating that Gli2 function is required primari ly in the stroma for proper ductal development. Delta Gli2 heterozygotes al so demonstrated an elevated frequency and severity of focal ductal dysplasi a relative to that of wild type littermate- and age-matched control animals . (C) 2001 Academic Press.