Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation

LEF/TCF DNA-binding proteins act in concert with activated beta-catenin, th e product of Wnt signaling, to transactivate downstream target genes, To pr obe the role of activated LEF/TCF transcription factor complexes in hair fo llicle morphogenesis and differentiation, we engineered mice harboring TOPG AL, a beta-galactosidase gene under the control of a LEF/TCF and beta-caten in inducible promoter, In mice, TOPGAL expression was directly stimulated b y a stabilized form of beta-catenin, but was also dependent upon LEF1/TCF3 in skin, During embryogenesis, TOPGAL activation occurred transiently in a subset of LEF1-positive cells of pluripotent ectoderm and underlying mesenc hyme, Downgrowth of initiated follicles proceeded in the absence of detecta ble TOPGAL expression, even though LEF1 was still expressed, While prolifer ative matrix cells expressed the highest levels of Lef1 mRNAs, LEF1 concent rated in the precursor cells to the hair shaft, where TOPGAL expression was co-induced with hair-specific keratin genes containing LEF/TCF-binding mot ifs. LEF1 and TOPGAL expression ceased during catagen and telogen, but reap peared at the start of the postnatal hair cycle, concomitant with precortex formation, In contrast to hair shaft precursor cells, postnatal outer root sheath expressed TCF3, but not TOPGAL, TCF3 was also expressed in the puta tive follicle stem cells, and while TOPGAL was generally silent in this com partment, it was stimulated at the start of the hair cycle in a fashion tha t appeared to be dependent upon stabilization of beta-catenin, Taken togeth er, our findings demonstrate that LEF1/TCF3 is necessary but not sufficient for TOPGAL activation, revealing the existence of positive and negative re gulators of these factors in the skin, Furthermore, our findings unveil the importance of activated LEF/TCF complexes at distinct times in hair develo pment and cycling when changes in cell fate and differentiation commitments take place.