The role of primary cilia in Townes-Brocks Syndrome

216 p.El Síndrome de Townes-Brocks (TBS1, MIM 107480 ) está causado por mutaciones en el gen SALL1, dando lugar, en la mayoría de los casos, a una proteína truncada. TBS se caracteriza por un espectro de malformaciones en dedos, oídos, corazón y riñones. Curiosamente, estos síntomas coinciden con aquellos observados en un número creciente de enfermedades y síndromes genéticos ligados a la formación y función del cilio primario conocidos como ciliopatías. Hasta ahora, el estudio del TBS se ha centrado en los defectos que, a nivel transcripcional, las mutaciones en SALL1 podrían ocasionar en el núcleo. Sin embargo, en esta tesis postulamos que las truncaciones en SALL1 podrían interferir con la función o señalización de los cilios debido a su interacción dominante negativa con proteínas del centrosoma o del cilio primario. Hemos descubierto que la proteína SALL1 truncada causa un incremento de la ciliogenesis y de la señalización de la vía Sonic-Hedgehog (Shh). También descubrimos que la forma truncada de SALL1 interactúa con los reguladores negativos de la ciliogénesis CCP110 y CEP97, posiblemente desestabilizándolos o desplazándolos del centríolo madre que da lugar al cilio primario y permitiendo, por tanto, la ciliogenesis. Además, SALL1 interactúa con la proteína LUZP1 que contiene cremalleras de leucina y tiene un papel fundamental durante el desarrollo. De hecho, el modelo de ratón knock-out de LUZP1 fenocopia algunas características asociadas con ciliopatías humanas, como defectos del tubo neural o de la formación del corazón. Nuestros datos respaldan el descubrimiento de que LUZP1 puede participar en la integración de la ciliogénesis y la dinámica de la actina durante el desarrollo.CICbioGUNE, Excelencia Severo Ocho

The role of primary cilia in Townes-Brocks Syndrome

216 p.El Síndrome de Townes-Brocks (TBS1, MIM 107480 ) está causado por mutaciones en el gen SALL1, dando lugar, en la mayoría de los casos, a una proteína truncada. TBS se caracteriza por un espectro de malformaciones en dedos, oídos, corazón y riñones. Curiosamente, estos síntomas coinciden con aquellos observados en un número creciente de enfermedades y síndromes genéticos ligados a la formación y función del cilio primario conocidos como ciliopatías. Hasta ahora, el estudio del TBS se ha centrado en los defectos que, a nivel transcripcional, las mutaciones en SALL1 podrían ocasionar en el núcleo. Sin embargo, en esta tesis postulamos que las truncaciones en SALL1 podrían interferir con la función o señalización de los cilios debido a su interacción dominante negativa con proteínas del centrosoma o del cilio primario. Hemos descubierto que la proteína SALL1 truncada causa un incremento de la ciliogenesis y de la señalización de la vía Sonic-Hedgehog (Shh). También descubrimos que la forma truncada de SALL1 interactúa con los reguladores negativos de la ciliogénesis CCP110 y CEP97, posiblemente desestabilizándolos o desplazándolos del centríolo madre que da lugar al cilio primario y permitiendo, por tanto, la ciliogenesis. Además, SALL1 interactúa con la proteína LUZP1 que contiene cremalleras de leucina y tiene un papel fundamental durante el desarrollo. De hecho, el modelo de ratón knock-out de LUZP1 fenocopia algunas características asociadas con ciliopatías humanas, como defectos del tubo neural o de la formación del corazón. Nuestros datos respaldan el descubrimiento de que LUZP1 puede participar en la integración de la ciliogénesis y la dinámica de la actina durante el desarrollo.CICbioGUNE, Excelencia Severo Ocho

LUZP1 Controls Cell Division, Migration and Invasion Through Regulation of the Actin Cytoskeleton

LUZP1 is a centrosomal and actin cytoskeleton-localizing protein that regulates both ciliogenesis and actin filament bundling. As the cytoskeleton and cilia are implicated in metastasis and tumor suppression, we examined roles for LUZP1 in the context of cancer. Here we show that LUZP1 exhibits frequent genomic aberrations in cancer, with a predominance of gene deletions. Furthermore, we demonstrate that CRISPR/Cas9-mediated loss of Luzp1 in mouse fibroblasts promotes cell migration and invasion features, reduces cell viability, and increases cell apoptosis, centriole numbers, and nuclear size while altering the actin cytoskeleton. Loss of Luzp1 also induced changes to ACTR3 (Actin Related Protein 3, also known as ARP3) and phospho-cofilin ratios, suggesting regulatory roles in actin polymerization, beyond its role in filament bundling. Our results point to an unprecedented role for LUZP1 in the regulation of cancer features through the control of actin cytoskeleton.We are grateful to the Fundacion Inocente, Inocente for their support. We also acknowledge funding by the grants BFU2017-84653-P (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), SAF2017-90900-REDT (UBIRed Program), and IT1165-19 (Basque Country Government). Additional support was provided by the Department of Industry, Tourism, and Trade of the Basque Country Government (Elkartek Research Programs) and by the Innovation Technology Department of the Bizkaia County. LB-B acknowledges POSTD19048BOZA (Fundacion Cientifica AECC). VM acknowledges PRE2018086230 (MINECO/FEDER, EU). AC acknowledges the Basque Department of education (IKERTALDE IT1106-16), the MCIU [PID2019-108787RB-I00 (FEDER/EU)], the AECC (IDEAS175CARR; GCTRA18006CARR), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/and the European Research Council (Starting Grant 336343, PoC 754627, Consolidator grant 819242). CIBERONC was co-funded with FEDER funds. We are also grateful to Maria Vivanco's lab for providing reagents

Virtual meeting, real and sound science: report of the 17 th Meeting of the Spanish Society for Developmental Biology (SEBD-2020)

The Spanish Society for Developmental Biology (SEBD) organized its 17th meeting in November 2020 (herein referred to as SEBD2020).This meeting, originally programmed to take place in the city of Bilbao, was forced onto an online format due to the SARS-CoV2, COVID-19 pandemic. Although, we missed the live personal interactions and missed out on the Bilbao social scene, we were able to meet online to pres- ent our work and discuss our latest results. An overview of the activities that took place around the meeting, the different scientific sessions and the speakers involved are presented here. The pros and cons of virtual meetings are discussed

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α–ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment

The role of primary cilia in Townes-Brocks Syndrome

216 p.El Síndrome de Townes-Brocks (TBS1, MIM 107480 ) está causado por mutaciones en el gen SALL1, dando lugar, en la mayoría de los casos, a una proteína truncada. TBS se caracteriza por un espectro de malformaciones en dedos, oídos, corazón y riñones. Curiosamente, estos síntomas coinciden con aquellos observados en un número creciente de enfermedades y síndromes genéticos ligados a la formación y función del cilio primario conocidos como ciliopatías. Hasta ahora, el estudio del TBS se ha centrado en los defectos que, a nivel transcripcional, las mutaciones en SALL1 podrían ocasionar en el núcleo. Sin embargo, en esta tesis postulamos que las truncaciones en SALL1 podrían interferir con la función o señalización de los cilios debido a su interacción dominante negativa con proteínas del centrosoma o del cilio primario. Hemos descubierto que la proteína SALL1 truncada causa un incremento de la ciliogenesis y de la señalización de la vía Sonic-Hedgehog (Shh). También descubrimos que la forma truncada de SALL1 interactúa con los reguladores negativos de la ciliogénesis CCP110 y CEP97, posiblemente desestabilizándolos o desplazándolos del centríolo madre que da lugar al cilio primario y permitiendo, por tanto, la ciliogenesis. Además, SALL1 interactúa con la proteína LUZP1 que contiene cremalleras de leucina y tiene un papel fundamental durante el desarrollo. De hecho, el modelo de ratón knock-out de LUZP1 fenocopia algunas características asociadas con ciliopatías humanas, como defectos del tubo neural o de la formación del corazón. Nuestros datos respaldan el descubrimiento de que LUZP1 puede participar en la integración de la ciliogénesis y la dinámica de la actina durante el desarrollo.CICbioGUNE, Excelencia Severo Ocho

Virtual meeting, real and sound science: report of the 17 th Meeting of the Spanish Society for Developmental Biology (SEBD-2020)

The Spanish Society for Developmental Biology (SEBD) organized its 17th meeting in November 2020 (herein referred to as SEBD2020). This meeting, originally programmed to take place in the city of Bilbao, was forced onto an online format due to the SARS-CoV2, COVID-19 pandemic. Although, we missed the live personal interactions and missed out on the Bilbao social scene, we were able to meet online to present our work and discuss our latest results. An overview of the activities that took place around the meeting, the different scientific sessions and the speakers involved are presented here. The pros and cons of virtual meetings are discussed

Targeting PML in triple negative breast cancer elicits growth suppression and senescence

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.ISSN:1350-9047ISSN:1476-540

Maternal inflammation induces immune activation of fetal microglia and leads to disrupted microglia immune responses, behavior, and learning performance in adulthood

Maternal inflammation during pregnancy can have detrimental effects on embryonic development that persist during adulthood. However, the underlying mechanisms and insights in the responsible cell types are still largely unknown. Here we report the effect of maternal inflammation on fetal microglia, the innate immune cells of the central nervous system (CNS). In mice, a challenge with LPS during late gestation stages (days 15-16-17) induced a pro-inflammatory response in fetal microglia. Adult whole brain microglia of mice that were exposed to LPS during embryonic development displayed a persistent reduction in pro-inflammatory activation in response to a re-challenge with LPS. In contrast, hippocampal microglia of these mice displayed an increased inflammatory response to an LPS re-challenge. In addition, a reduced expression of brain-derived neurotrophic factor (BDNF) was observed in hippocampal microglia of LPS-offspring. Microglia-derived BDNF has been shown to be important for learning and memory processes. In line with these observations, behavioral- and learning tasks with mice that were exposed to maternal inflammation revealed reduced home cage activity, reduced anxiety and reduced learning performance in a T-maze. These data show that exposure to maternal inflammation during late gestation results in long term changes in microglia responsiveness during adulthood, which is different in nature in hippocampus compared to total brain microglia. (C) 2017 Elsevier Inc. All right