Epidermal YAP Activity Drives Canonical WNT16/β-catenin Signaling to Promote Keratinocyte Proliferation in vitro and in the Murine Skin

The skin constantly self-renews throughout adult life. Wnt/β-catenin signaling plays a key role in promoting keratinocyteproliferation in the hair follicles and in the interfollicular epidermis.A recent report demonstrated that epidermal YAP activity drives β-cateninactivation to promote keratinocyte proliferation in the murine skin.However, it remains unclear whether this is caused by paracrineactivation of canonical Wnt signaling or through other YAP/β-cateninregulatory interactions. In the present study, we found that XAV939-inhibition of canonical WNT signaling in skin of YAP2-5SA-ΔC miceresulted in diminished β-catenin activation, reduced keratinocyteproliferation, and a mitigation of the hyperplastic abnormalities in theinterfollicular epidermis, signifying a canonical WNT ligand-dependentmechanism. Our subsequent analyses determined that WNT16 is produced inresponse to YAP activity in keratinocytes both in vitro and in vivo, andthat WNT16 drives HaCaT keratinocyte proliferation via canonical WNT16/β-catenin signaling. We conclude that under normal physiological conditionsWNT16 is the paracrine WNT ligand secreted in response to epidermal YAPactivity that promotes cell proliferation in the interfollicularepidermis. This study delineates a fundamental YAP-driven mechanism thatcontrols normal skin regeneration, and that may be perturbed in humanregenerative disease displaying increased YAP and WNT signaling activity

Epidermal YAP2-5SA-DeltaC drives beta-catenin activation to promote keratinocyte proliferation in mouse skin in vivo

The epidermis is a highly regenerative tissue. YAP is a pivotal regulator of stem/progenitor cells in tissue regeneration, including in the epidermis. The molecular mechanisms downstream of YAP that activate epidermal cell proliferation remain largely unknown. We found that YAP and β-catenin co-localize in the nuclei of keratinocytes in the regenerating epidermis in vivo and in proliferating HaCaT keratinocytes in vitro. Inactivation of YAP in HaCaT keratinocytes resulted in reduced activated β-catenin and reduced keratinocyte numbers in vitro. In addition, we found that in the hyperplastic epidermis of YAP2-5SA-ΔC mice, the mutant YAP2-5SA-ΔC protein was predominantly localized in the keratinocyte nuclei and caused increased expression of activated nuclear β-catenin. Accordingly, β-catenin transcriptional activity was elevated in the skin of live YAP2-5SA-ΔC/TOPFLASH mice. Lastly, loss of β-catenin in basal keratinocytes of YAP2-5SA-ΔC/K14-creERT/CtnnB1(-/-) mice resulted in reduced proliferation of basal keratinocytes and a striking rescue of the hyperplastic abnormalities. Taken together, our work shows that YAP2-5SA-ΔC drives β-catenin activity to promote basal keratinocyte proliferation in the mouse skin in vivo. Our data shine new light on the etiology of regenerative dermatological disorders and other human diseases that display increased YAP and β-catenin activity.Bassem Akladios, Veronica Mendoza-Reinoso, Michael S. Samuel, Edna C. Hardeman, Kiarash Khosrotehrani, Brian Key and Annemiek Beverda

Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population

OAJ-2003Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica - Concyte

Aplicación de criterios bioecológicos para la identificación, caracterización y establecimiento de límites funcionales en humedales de las sabanas inundables de la Orinoquia

En este libro se consolida entonces todo el proceso de caracterización biológica de los humedales de los llanos de Hato Corozal, la identificación de las especies clave para establecer los límites funcionales de los humedales y se presentan perfiles estructurales que permiten identificar la presencia de especies, su zonación ecológica y variación estacional en todos los tipos humedal, un trabajo sin duda alguna que espera contribuir con el debate global acerca de la conservación, uso y manejo de los humedales en tiempos de adaptación al cambio climático.Bogotá, D. C., ColombiaInstituto de Investigación de Recursos Biológicos Alexander von Humbold