Lhx2 Maintains Stem Cell Character in Hair Follicles

Abstract

During embryogenesis, stem cells are set aside to fuel the postnatal hair cycle and repair the epidermis after injury. To define how hair follicle stem cells are specified and maintained in an undifferentiated state, we developed a strategy to isolate and transcriptionally profile embryonic hair progenitors in mice. We identified Lhx2 as a transcription factor positioned downstream of signals necessary to specify hair follicle stem cells, but upstream from signals required to drive activated stem cells to terminally differentiate. Using gain- and loss-of-function studies, we uncovered a role for Lhx2 in maintaining the growth and undifferentiated properties of hair follicle progenitors.

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

“…EDA and EDAR interact with members of the bone morphogenetic protein (BMP) family, some of which are inhibitory to follicle development, to establish follicle patterning (Mou et al, 2006;Pummila et al, 2007). In the earliest stages of follicle initiation, there has been an emphasis on determining the molecular factors that distinguish the placode versus the interfollicular epidermis (Nowak et al, 2008;Rhee et al, 2006). Two pathways that have an essential role in these cell fate decisions include EGF and KGF (FGF7 -Mouse Genome Informatics) (Beer et al, 2000;du Cros, 1993;Peus and Pittelkow, 1996;Schneider et al, 2008, Guo et al, 1996.…”

Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

“…Different transcription factors known to regulate cell fate specification such as Lhx3, Atoh1/Math1, Mash1, or Islet1 are preferentially expressed in neonatal mouse MCs (Haeberle et al, 2004). Atoh1/Math1 is expressed in developing and adult MCs (Ben-Arie et al, 2000;Lumpkin et al, 2003;Haeberle et al, 2004) and in embryonic P-cadherinpositive hair progenitor cells (Rhee et al, 2006). Conditional deletion of Atoh1 in all cells of the developing trunk region using Hoxb1-CRE resulted in the absence of MC specification in the paw and the back skin epidermis, but MCs of the whisker region were still present (Maricich et al, 2009).…”

“…The cells coexpressing K14 and MC markers during embryonic development may be the previously described transitional cells seen by electron microscopy, which were thought to represent the transition from epidermal cells to MCs (Tachibana and Nawa, 1980). Furthermore, the demonstration that early specified MCs coexpress P-cadherin, a marker of embryonic hair follicle (HF) progenitors (Rhee et al, 2006), and the absence of MC specification in Tabby mutant mice (Vielkind et al, 1995), which present defects in HF morphogenesis, suggest that HF progenitors and MC specification could be tightly linked.…”

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

“…Both Wnt and Shh pathways are essential for HF development and cycling [for review, see 32 ], and, if abnormally activated, result in the development of a number of epithelial tumors. 26,[33][34][35][36][37][38] Interestingly, cells localized at the tumor placodes showed expression of the keratin 15 mRNA and Lhx2 protein, markers of the epithelial stem cells, 39,40 while their expression in fully developed tumors strongly decreased and was seen only in clusters of cells at the tumor periphery ( Figure 3, A and B). Keratinocytes of the tumor placodes also showed increased expression of the Wnt10b, Lef1, and nuclear ␤-catenin compared with the cells of fully developed tumors (Figure 3, A and B) and to the bulge cells of normal anagen HFs (data not shown).…”