Cell Death Dis. 2018 Dec 5;9(12):1183. doi:10.1038/s41419-018-1205-6; PMID: 30518789; PMCID: PMC6281643Cell Death Disease 228x300


Fuertes-Alvarez, Sandra; Maeso-Alonso, Laura; Villoch-Fernandez, Javier; Wildung, Merit; Martin-Lopez, Marta; Marshall, Clayton; Villena-Cortes, Alberto J; Diez-Prieto, Inmaculada; Pietenpol, Jennifer A; Tissir, Fadel; Lize, Muriel; Marques, Margarita M; Marin, M Carmen.


Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton


El factor de transcripción p73, perteneciente a la familia de supresores tumorales p53, es un regulador esencial del desarrollo del Sistema Nervioso. Durante mucho tiempo se pensó que esta modulación tenía que ver exclusivamente con su papel en la regulación de la autorrenovación celular. Sin embargo, su función va mucho más allá , siendo esencial en el mantenimiento de la estructura del nicho neurogénico subventricular. En este trabajo se desvela el papel esencial de p73 en el establecimiento de la Polaridad Celular Planar de las células ependimarias, que es la organización y polarización del citoesqueleto celular de la zona apical de las células multiciliadas que tapizan los ventrículos cerebrales. En ausencia de p73, se altera la organización y polarización del citoesqueleto de estas células, así como las proteínas implicadas en todo este proceso. Todo ello conlleva la completa desorganización de los cilios, impidiendo su movimiento coordinado y la alteración de las funciones de las células ependimarias que dependen del movimiento del líquido cefalorraquídeo a su paso por los ventrículos cerebrales: desde evitar su acumulación en este punto hasta la generación de gradientes de moléculas necesarias para las células troncales de este nicho, y el correcto transporte de los neuroblastos hasta el bulbo olfatorio. Estos resultados señalan a p73 como un importante regulador de la arquitectura epitelial, pero además indican un posible papel en transporte y migración celular mediante su implicación en la regulación del citoesqueleto.






El grupo de investigación de las Dras. Carmen Marín y Margarita Marqués, localizado en el Instituto de Biomedicina de la Universidad de León, se centra en el estudio funcional de la familia génica p53, importante por su conocido papel en supresión tumoral, y más concretamente de la proteína p73, esencial en el desarrollo y mantenimiento funcional del Sistema Nervioso. Esta importante familia de factores de transcripción está implicada en la regulación de múltiples procesos biológicos tanto en células troncales como en células somáticas. Este grupo ha aportado importantes avances en el conocimiento del papel de p73 en aspectos tan importantes como la diferenciación eritroide (Marques-Garcia et al 2009), la diferenciación endotelial (Fernandez-Alonso et al., 2011), la autorrenovación y diferenciación de las células troncales neurales (Gonzalez-Cano et al., 2010; Gonzalez-Cano et al., 2013); su implicación en la inducción de la pluripotencia (Martin-Lopez et al., 2017), el desarrollo del nicho neurogénico subventricular (Gonzalez-Cano et al., 2016) y el establecimiento de la polaridad mediante la regulación del citoesqueleto celular (Fuertes-Alvarez et al., 2018). Actualmente, están centrados en conocer el papel de p73 en el establecimiento y mantenimiento de las uniones intercelulares de células endoteliales y en la migración de las células troncales de glioblastoma.

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