Inactivation of histone chaperone HIRA unmasks a link between normal embryonic development of melanoblasts and maintenance of adult melanocyte stem cells

Abstract

Histone chaperone HIRA is thought to play a role in both early development and aging, but little is known about connections between the two processes. Here, we explore this relationship using a lineage-specific knockout mouse model, TyrCre::Hirafl/fl, in which HIRA is deficient in the pigmentary system consisting of embryonic melanoblasts, postnatal melanocytes and melanocyte stem cells (McSCs). Hira knockout leads to reduced melanoblast numbers during embryogenesis, but wild type numbers of melanocytes at birth, normally functioning juvenile and young adult McSCs, and only a very mildly hypopigmented first hair coat. However, on closer analysis, Hira knockout melanocytic cells of newborn mice exhibit molecular markers characteristic of cell aging and proliferative deficits. As they age, TyrCre::Hirafl/fl mice display marked defects in McSC maintenance and premature hair graying. Importantly, these defects are only observed when HIRA is inactivated during embryogenesis, not post-natally. This genetic model illustrates how normal embryonic development lays the foundation for maintenance of adult tissue specific stem cells and so suppression of degenerative phenotypes of aging.