Genetic analyses of the roles of Sox2 and Sox18 in mouse hair development and growth

Abstract

The mouse pelage hair consists of three types of hair coined primary (guard), secondary (awls and auchenes) and tertiary (zigzag) hair. They display distinct morphologies and are induced consecutively during hair morphogenesis. Previously two identified regulatory mouse mutants, Yellow submarine (Ysb) and Light coat and circling (Lcc) which the chromosomal rearrangements have disrupted the cis-acting regulatory elements of Sox2; resulting in the loss of Sox2 expression in the inner ear. The mutants displayed lighter hair coat color due to a reduction in the proportion of secondary hair and increased proportion of tertiary hair. Sox18 null mutants display darker coat colour and reduced proportion of zigzag hair. To dissect the underlying mechanisms of the phenotypes in hair type specification in 〖Sox2〗^Ysb and 〖Sox2 〗^Lcc mutants and the role of Sox2 and Sox18 in regulating the process; the expression of Sox2 in the hair follicle and the change in the density of hair types in mutants were analyzed.

I have identified the expression pattern of Sox2 in the dermal papilla (DP) of the hair follicle and verified its down-regulation in 〖Sox2〗^Ysband 〖Sox2 〗^Lcc mutants. The DP at the base of hair follicle is the signaling center for the regulation of hair development. Sox2 is specifically expressed in the DP of primary and secondary but not in tertiary hair while Sox18 is expressed in the DP of all hair types. Analysis of Sox2 mutants showed that the number of secondary hair was normal at induction but was reduced and accompanied by an increase in tertiary hair in adult mice. The number of tertiary hair was reduced in Sox18 null mutants. To gain insight into the molecular basis of hair type specification and potential targets of Sox2 in the regulation, gene expression profile in DP cells of 〖Sox2 〗^(EGFP/+)and 〖Sox2 〗^(EGFP/Ysb) mice was examined; the data suggests that genes in the Wnt and BMP signalling pathway were down-regulated in Sox2 mutants; while Runx3 and Corin may act downstream of Sox2 in regulating hair type specification and pigmentation.

Hair follicles enter cycles of growth and regression throughout life during the hair cycle. Sox2 was only expressed in the growth phase while Sox18 was persistently expressed throughout the hair cycle. I further asked if Sox2 and Sox18 regulate post-natal hair development by analysing the expression pattern of Sox2 and Sox18 in wildtype mice and mutants throughout the hair cycle and the progression of hair growth in the mutants. The growth phase of the first hair cycle was extended in Sox2 mutants while the hair cycle in Sox18 null mutants was normal. Cell proliferation was compromised during hair regeneration leading to a delay in hair regeneration in Sox2 mutants.

Sox2 and Sox18 showed overlapping expression in the DP and both regulate hair type specification. To test if Sox2 and Sox18 synergistically regulate hair development, the 〖Sox2〗^(Ysb/Ysb);〖Sox18〗^(-/-) mutants have been generated. Hair morphogenesis and differentiation were impaired; while the number of tertiary hair was increased with reduced number of secondary hair, which phenocopied that of Sox2 mutants. In conclusion, the results suggest that Sox2 and Sox18 functions synergistically on the regulation of hair growth and differentiation.