Hoxc13 has been shown to be essential for proper hair shaft differentiation as Hoxc13 gene-targeted (Hoxc13tm1Mrc) mice completely lack external hair. Because of the phenotypic parallels to the Foxn1nu (nude) mutant mice, we tested whether Hoxc13 and Foxn1 act in a common pathway of hair follicle (HF) differentiation. We show that the alopecia exhibited by both the Hoxc13tm1Mrc and Foxn1nu mice is due to strikingly similar defects in hair shaft differentiation and that both mutants suffer from a severe nail dystrophy. These similarities are consistent with the overlap of Hoxc13 and Foxn1 expression patterns in the HF and nail matrix. DNA microarray analysis of scapular skin from Hoxc13tm1Mrc mutant (mut) compared to wild type (wt) mice identified Foxn1 as significantly down-regulated along with numerous hair keratin genes. This Foxn1 down-regulation apparently reflects the loss of direct transcriptional control by HOXC13 as indicated by our results obtained through co-tranfection and chromatin immunoprecipitation (ChIP) assays.