MERLIN MEDIATED REGULATION OF HAIR FOLLICLE MORPHOGENESIS

Epidermal homeostasis is paramount for the ongoing function of the skin as the primary barrier between a mammalian organism and the external environment. Homeostasis is achieved through a complex and delicate balance of cell death, cell proliferation and cell differentiation. Critical for regeneration and maintenance of the skin are epidermal stem cells. Within the epidermis two distinct stem cell compartments exist, the bulge and interfollicular/basal stem cell niches, which play a central role in the regeneration of the epidermis through self-renewal and contribution to the differentiated cells of the epidermis. The bulge stem cell niche is established early in epidermal development. The establishment and proper functioning of this specialized cell compartment is dependent on the stem cells ability to receive and respond to external signals such as Wnt signaling. Disruption in the ability of stem cells to integrate these signals can result in disruption in hair follicle architecture, lack of differentiated cells and disease. Cells are able to transmit extracellular signals from the cell membrane to the actin cytoskeleton through the adherens junctions (AJ). The AJ is composed of the core proteins E-cadherin, β-catenin and α-catenin. α-catenin acts to tether the AJ complex to the actin cytoskeleton. In addition to the core AJ proteins, proper formation and maturation of the AJ is dependent upon a multi-protein complex called the junctional polarity complex (JPC) composed of a-catenin, the polarity proteins Par3 and aPKC as well as the tumor suppressor Merlin, the protein product of the Nf2 gene. Merlin plays a pivotal role in the function of the JPC by bridging Par3 to a-catenin and in the absence of Merlin the interaction between Par3 and α-catenin is unable to promote formation of functional AJs and tight junctions (TJ). Mice with a deletion of Merlin in the epidermis are unable to form an epidermal barrier due to the loss of TJ in addition to having alterations in basal cell polarity. Post-natal Merlin mutant mice have alterations in differentiation as well as stratification defects of the epidermis. Here we show that in addition to the disruptions in epidermal stratification there is also an alteration in planar polarity of the developing hair follicles combined with defects in hair follicle formation in Merlin-deficient skin. Disruptions in polarity of the developing hair placodes are observed as early as embryonic day 14.5, as well as defects in cellular orientation and organization of the early placodes as early as E13.5 Although the requirement of the bulge stem cell niche in maintaining the hair follicle and epidermis is well characterized, the establishment of this niche is not well understood. This study will describe a role for Merlin in the development of the bulge stem cell niche through establishment of polarity. This work will lead to a better understanding of how stem cell niches are initially established and organized through interactions at cellular junctions and the actin cytoskeleton providing new insight into how stem cell niches are regulated in epithelial tissues throughout the body