The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.

Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2Δ43) caused mislocalization of Evc/Evc2Δ43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2(-/-) chondrocytes. Moreover, Evc silencing in Sufu(-/-) cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation.

Diagnóstico clínico y citopatológico del virus del herpes simple bucal en pacientes con trasplante de riñón / Clinical and cytopathological diagnosis of oral herpes simplex in patients with kidney transplant

RESUMEN Fundamento: el uso de fármacos potencialmente inmunosupresores ha permitido una mejoría en la sobrevida y calidad de vida de los enfermos con trasplante renal, pero favorecen el deterioro del sistema inmunitario del organismo y la aparición de diversas infecciones víricas oportunistas, entre ellas el herpes simple, que es contagiosa e incurable y responsable del inicio de múltiples lesiones que afectan la piel y las mucosas. Objetivo: identificar las manifestaciones clínicas y citopatológicas de las lesiones bucales provocadas por el virus del herpes simple en pacientes con trasplante de riñón. Métodos: se realizó un estudio descriptivo y transversal, con un universo de 50 pacientes con trasplante renal y diagnóstico clínico de infección herpética, asistidos en la consulta estomatológica del Policlínico de Especialidades del Hospital Provincial Clinicoquirúrgico Universitario Saturnino Lora Torres, de Santiago de Cuba, desde noviembre de 2014 hasta igual mes de 2016. Para la recolección del dato primario se confeccionó una encuesta que incluía las siguientes variables: edad, sexo, localización topográfica, síntomas clínicos y factores predisponentes de la lesión, así como alteraciones celulares presentes en el epitelio de la boca. Se realizó estudio citopatológico de las lesiones. Resultados: en la serie predominó el sexo masculino y el dolor como síntoma clínico, el sitio de mayor ocurrencia fue el bermellón del labio inferior; la presencia de células epiteliales gigantes multinucleadas con cuerpos de inclusiones intranucleares y necrosis de células infectadas, respectivamente, fueron los hallazgos citológicos más importantes. Conclusiones: en la totalidad de los pacientes se reveló en los exámenes clínicos y citopatológicos la presencia de lesiones bucales compatibles con la infección por virus del herpes simple.

ABSTRACT Foundation: the use of medications potentially inmunodepressors has allowed an improvement in the longer and quality life in patients with renal transplant, but favor the deterioration of the immune system and the appearance of diverse opportunistic viral infections, among them herpes simplex, which is contagious and incurable and responsible of the starting of multiple lesions which affect the skin and mucose. Objective: to identify the clinical and cytopathological manifestations of oral lesions caused by the herpes simplex virus in patients with kidney transplant. Methods: a descriptive cross study, with a universe of 50 patients with renal transplant diagnosed clinically with a herpes infection, assisted in a dentistry consultation of the Polyclinic of Specialties at the Clinical Surgical University Hospital Saturnino Lora Torres, Santiago of Cuba, from November 2014 to the same the month 2016. For primary data collection a survey was designed including: age, sex, topographic location, clinical symptoms and lesion predisposing factors, so as present cellular disturbances in the oral epithelium. A cytopathological study of the lesions was performed. Results: the male sex and pain as a clinical symptom predominated, the most frequent location was the vermillon of the lower lip, the presence of giant epithelial multinucleated cells with bodies of intranuclear inclusions, and necrosis of infected cells, respectively, were the most important cytologic findings. Conclusion: in all of the patients there were oral lesions compatible with infection by the virus of herpes simplex.