Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular, Cellular, and Developmental Biology

First Advisor

Myung, Peggy

Abstract

Developmental morphogenesis requires cells to balance proliferation with differentiation, often regulated by multiple signaling pathways. While most studies consider these pathways as additive, less is known about how they interact to regulate fate transitions. In this dissertation, I use the hair follicle dermal condensate (DC), the first differentiated mesenchymal population of the skin with the ability to instruct new hair growth, to study morphogens interact to regulate the dermal mesenchyme.Wnt and SHH are necessary and sufficient for DC formation, during which cell cycle exit with molecular DC gene expression occur simultaneously. Interestingly, high Wnt alone is sufficient to induce cell cycle exit, whereas expression of DC genes requires both Wnt and SHH activity, suggesting these two processes are distinctly regulated. Mechanistically, SHH cell-autonomously boosts Wnt activity, while high Wnt activity reduces the chromatin occupancy of repressive SHH transcription factor to induce exit, effectively coupling the two processes by coupling SHH and Wnt morphogen levels. I further give evidence that relative Wnt and SHH levels also can diversify non-DC mesenchymal fates. Finally, I examine whether Wnt and SHH activity can re-emerge to induce DC fates in adult human skin. Benign lesions contain Wnt-active, SHH-active DC-like structures that can induce primordial hair follicle differentiation, whereas more malignant tumors such as basal cell carcinomas lack DCs or any sign of differentiation. Together, this work defines how Wnt and SHH are integrated to specify diverse mesenchymal lineages and can be resurrected in humans, highlighting principles with relevance for organogenesis, regeneration, and tumorigenesis.

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