Jagged 1 is a β-catenin target gene required for ectopic hair follicle formation in adult epidermis

Abstract

The Wnt and Notch signalling pathways regulate hair follicle maintenance,but how they intersect is unknown. We show that Notch signalling is active in the hair follicle pre-cortex, a region of high Wnt activity, where commitment to hair lineages occurs. Deletion of jagged 1 (Jag1) results in inhibition of the hair growth cycle and conversion of hair follicles into cysts of cells undergoing interfollicular epidermal differentiation. Conversely, activation of Notch in adult epidermis triggers expansion of the base of the hair follicle, sebaceous gland enlargement and abnormal clumping of the follicles. In adult epidermis, the induction of new hair follicle formation by β-catenin is prevented by blocking Notch signalling pharmacologically or through Jag1 deletion. Conversely, activation of both pathways accelerates growth and differentiation of ectopic follicles.β-catenin stimulates Notch signalling by inducing Jag1transcription. We conclude that the Notch pathway acts downstream of the Wnt/β-catenin pathway to determine epidermal cell fate.

Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling

“…The Jagged1 gene, which encodes a Notch ligand, has been reported to be transcriptionally activated by the b-catenin/TCF4 complex, a downstream effector in Wnt signaling (Estrach et al, 2006;Katoh and Katoh, 2006). We confirmed that Jagged1 was also a target of Wnt signaling in colon cells by showing that induction of dominant-negative TCF4 in LS174 T-cells inhibited the expression of Jagged1 (Supplemental Figure 1).…”

“…The restricted expression of Jagged1 in the normal intestinal mucosa may result from random asymmetric division of intestinal secretory precursors, as described for another Notch ligand, Delta, in adult Drosophila midgut (Ohlstein and Spradling, 2006). There was not a direct correspondence between b-catenin nuclear translocation in the tumors and Jagged1 expression, despite the fact that data in the literature suggest, and in vitro data reported here demonstrate, that Jagged1 can be regulated by Wnt signaling in colon epithelial cells (Estrach et al, 2006;Katoh and Katoh, 2006), conclusions that were extended by Rodilla et al (2009) while this paper was under review. Moreover, we observed that this heterogeneity in Jagged1 expression extended to tumors in the congenic Apc Min/ þ and Apc 1638N/ þ models, two mouse strains in which elevated Wnt signaling initiates intestinal tumor development.…”

“…This emphasizes the importance of understanding the functional and regulatory interactions among Notch and Wnt signaling in intestinal cells and tumorigenesis. As regards regulatory interactions, it has been shown that a Notch ligand, Jagged1, is transcriptionally controlled by the b-catenin/TCF4 complex in the hair follicle of the inner ear (Estrach et al, 2006), and similar results were found by bioinformatic analysis of the promoter of the human Jagged1 sequence (Katoh and Katoh, 2006). Since elevated Wnt signaling, usually due to mutations in the Apc gene, drive colon tumor development, we evaluated how this was linked to Jagged1 expression.…”

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

“…Yet, the lack of mesenchymal cells derived from the dermomyotome may account for the lack of hair in the specific area. It is, of course, possible that the increase in ␤-catenin within the epidermis of the remaining body may lead to an increase in hair growth, as has been seen in other studies (Gat et al, 1998;Estrach et al, 2006).…”

Biology of Human Hair: Know Your Hair to Control It

“…In the absence of Notch signaling, the hair shaft still forms and contains appropriately positioned cells expressing markers for each fate; however, because IRS cells fail to adhere to each other, the follicular architecture cannot be sustained, which leads to the transformation of these aberrant HF into epidermal cysts [92][93][94][95]. Very recently, Demehri and Kopan [96] proposed that Notch acting on bi-potential bulge stem cells, or their uncommitted migratory descendents, plays an inhibitory role in preventing bulge stem cells from differentiating into epidermal cells, thus ensuring the follicular fate.…”