The researchers constructed mouse models for WNT10A-associated HED by deleting the Wnt10a gene. The mutant mice displayed the same symptoms as HED patients with severe loss-of-function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness.

We showed "that -catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails, and sweat ducts, the authors wrote. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by the loss of the transcription factor KLF4. We found that -catenin interacts directly with region-specific LEF/TCF [lymphoid enhancer factor/T-cell factor] factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity.

Interestingly, the UPenn team also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity.

"Our studies took us back and forth between human patients and our mouse model," said Dr. Millar. "Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments."

Dr. Millar and her colleagues showed that decreased proliferation and keratin 9 expression in the absence of WNT10A resulted from the failure of signaling through a well-characterized pathway that stabilizes -catenin, allowing it to enter the cell nucleus and activate gene transcription. These findings indicate that small-molecule drugs that activate the -catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male-pattern baldness.

Read more:
Potential Baldness Pathway Uncovered while Studying Rare Skin ... - Genetic Engineering & Biotechnology News

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