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Hair is important for thermoregulation, physical protection, sensory activity, seasonal camouflage and social interactions. Hair is produced in hair follicles (HFs), complex mini-organs in the skin devoted to this task. HFs are formed during embryonic development (morphogenesis) and new hair is continuously generated throughout life since the postnatal HF goes through cycles of regression (catagen), quiescence (telogen) and growth (anagen). The transcriptional regulation of this process is not well understood. The LIM-homeodomain transcription factor Lhx2 has previously been shown to be critically involved in epithelial-mesenchymal interactions during development of various organs and a potent regulator of stem cell function. We therefore elucidated the expression pattern and function of Lhx2 during hair formation.

Lhx2 is expressed during both morphogenesis and anagen in cells scattered in the outer root sheath and in a subpopulation of the matrix cells in the proximal part of the hair bulb. Matrix cells are proliferating progenitor cells that differentiate into the components of the HF including the hair shaft. Expression is turned off during telogen, however Lhx2 expression reappears in the secondary hair germ immediately prior to initiation of the anagen stage. In contrast to previously published results Lhx2 appears to be expressed by progenitor cells distinct from those in the stem cell niche in the bulge region. The developmental-, stage- and cell-specific expression pattern of Lhx2 suggests that Lhx2 is involved in the generation and regeneration of hair.

To test our hypothesis we used different genetically modified mouse strains. First we studied the effect of over-expression of Lhx2 in the HFs using a mouse model where transgenic Lhx2 expression could be induced in dorsal skin. Using this model we could show that Lhx2 expression is sufficient to induce anagen. To analyze the consequence of lack-of-function of Lhx2 we developed a mouse model where it is possible to conditionally inactivate Lhx2 and a mouse strain harbouring a hypomorphic allele of Lhx2. Mice where Lhx2 was conditionally inactivated in postnatal HFs were unable to regrow hair on a shaved area whereas all controls did regrow their hair. The mutant HFs initiated anagen but were unable to produce normal hair shafts. Thus Lhx2 is required for postnatal hair formation. We used the mouse strain carrying a hypomorphic allele of Lhx2 to study the role of Lhx2 during HF morphogenesis. Embryos homozygous for the hypomorphic allele form significantly less HFs compared to control embryos, and the HFs that do form in the mutant embryos appear to be developmentally arrested. These results suggest that Lhx2 is also important during HF morphogenesis. Thus, Lhx2 is an essential positive regulator of hair generation and regeneration.