GATA-3: an unexpected regulator of cell lineage determination in skin

Abstract

Multipotent skin stem cells give rise to epidermis and its appendages, including the hair follicle. The Lef-1/Tcf family of Wnt-regulated transcription factors plays a major role in specification of the hair shaft, but little is known about how the equally important hair channel, the inner root sheath (IRS), develops in concert to shape and guide the hair. In a microarray screen to search for transcriptional regulators of hair follicle morphogenesis, we identified GATA-3, a key regulator of T-cell lineage determination. Surprisingly, this transcription factor is essential for stem cell lineage determination in skin, where it is expressed at the onset of epidermal stratification and IRS specification in follicles. GATA-3-null/lacZ knock-in embryos can survive up to embryonic day 18.5 (E18.5), when they fail to form the IRS. Skin grafting unveiled additional defects in GATA-3-null hairs and follicles. IRS progenitors failed to differentiate, whereas cortical progenitors differentiated, but produced an aberrant hair structure. Curiously, some GATA-3-null progenitor cells expressed mixed IRS and hair shaft markers. Taken together, these findings place GATA-3 with Lef-1/Wnts at the crossroads of the IRS versus hair shaft cell fate decision in hair follicle morphogenesis. This newfound function for GATA-3 in skin development strengthens the parallels between the differentiation programs governing hair follicle and lymphocyte differentiation.

GATA-3 expression in normal and pathological human skin conditions

“…In none of the 37 pathological skin conditions investigated expression of GA-TA-3 was observed. The finding of GATA-3 expression in the matrix of the hair follicle is consistent with a study by Kaufman CK et al (14), which has shown that this transcription factor is essential for stem cell lineage determination in skin and for directing epidermal stem cells to become inner root sheath cells. Furthermore, GATA-3-null embryos show aberrations in hair follicle morphogenesis that include not only structural defects in the inner root sheath and in the hair shaft, but also molecular defects in cell lineage determination (14).…”

“…The finding of GATA-3 expression in the matrix of the hair follicle is consistent with a study by Kaufman CK et al (14), which has shown that this transcription factor is essential for stem cell lineage determination in skin and for directing epidermal stem cells to become inner root sheath cells. Furthermore, GATA-3-null embryos show aberrations in hair follicle morphogenesis that include not only structural defects in the inner root sheath and in the hair shaft, but also molecular defects in cell lineage determination (14). Although GA-TA-3 has been recently described to be localized in the spinous layer of the interfollicular epidermidis (16), in our study we didn't find the expression of GATA-3 in the spinous layer probably because of the different technique used.…”

“…Moreover, transgenic T cell expression of a dominant-negative GATA-3 allele attenuates allergic inflammation in a murine model of asthma, with decreased eosinophilia, mucus production, and IgE levels associated with decreased IL-4, IL-5, and IL-13 production (12,13). Furthermore, a relatively recent investigation has demonstrated that this transcription factor is essential for stem cell lineage determination in skin (14). Expression of GATA-3 in vivo has been investigated in normal and pathological lymphoid tissues by immunohistochemical staining of frozen material (15).…”

p63 in epithelial development

“…2). GATA-3 is an important mediator of skin and hair development [47], although its specific function in epidermal development and differentiation has not yet been established. However, Np63 can transactivate IKK only indirectly via GATA-3 (Fig.…”

The significance of GATA3 expression in breast cancer: a 10-year follow-up study

“…GATA3 regulates lineage determination of many cell types. These include neurons of the sympathetic nervous system, T helper cells, the inner root sheath of hair follicles, fat cells, nephritic ducts of the kidney, and the ear cochleae [4,5]. Fetal mice cannot survive to term without GATA3 [6].…”