https://hdl.handle.net/11000/479 2026-05-06T09:50:55Z 2026-05-06T09:50:55Z Martinez-Morga, Marta Garrigós, Daniel Rodriguez-Montero, Elena Pombero, Ana García-Lopez, Raquel Martínez, Salvador https://hdl.handle.net/11000/39847 2026-05-06T01:06:43Z 2026-05-05T18:50:41Z

Título : Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression Autor : Martinez-Morga, Marta; Garrigós, Daniel; Rodriguez-Montero, Elena; Pombero, Ana; García-Lopez, Raquel; Martínez, Salvador Resumen : Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.

2026-05-05T18:50:41Z Garrigos, Daniel Martínez-Morga, Marta Pombero, Ana García-Lopez, Raquel Pastor, Diego Riquelme, Dolores Blanquer Blanquer, Miguel Iniesta, Francisca Valdor, Rut Geijo-Barrientos, Emilio Hargus, Gunnar Moraleda, Jose M. Martínez, Salvador https://hdl.handle.net/11000/39846 2026-05-06T01:06:42Z 2026-05-05T18:48:02Z

Título : Chaperone mediated autophagy is deficient in spinal motoneurons of ALS patients with TDP-43 proteinopathy Autor : Garrigos, Daniel; Martínez-Morga, Marta; Pombero, Ana; García-Lopez, Raquel; Pastor, Diego; Riquelme, Dolores; Blanquer Blanquer, Miguel; Iniesta, Francisca ; Valdor, Rut; Geijo-Barrientos, Emilio; Hargus, Gunnar; Moraleda, Jose M.; Martínez, Salvador Resumen : Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons (MNs), ultimately resulting in paralysis and respiratory failure within 3 to 5 years of onset. Fewer than 10% of ALS cases are familial (fALS), while the vast majority are sporadic (sALS) with an unknown etiology. A pathological hallmark of ALS is the accumulation of misfolded TDP-43 protein aggregates within MNs. Although TDP-43 is known to be degraded via chaperone-mediated autophagy (CMA), the status of CMA activity in sALS has not been previously explored. To investigate this, we analyzed CMA in human spinal cord tissue by assessing the expression of LAMP2A, a key lysosomal receptor and marker of CMA activity. In control samples, spinal cord MNs exhibited robust LAMP2A expression. In contrast, MNs from sALS patients showed a marked reduction in LAMP2A levels, coinciding with the presence of TDP-43 pathology. Notably, analysis of LC3, a marker of macroautophagy, revealed no significant differences in expression between control and sALS MNs. Interestingly, MNs within the Onuf’s nucleus, a population known to be resistant to degeneration in ALS, retained normal LAMP2A expression and did not exhibit TDP-43 aggregation in sALS cases. These findings demonstrated that CMA is essential for the clearance of TDP-43 in spinal cord MNs and that its dysfunction may contribute to the pathogenesis of sALS. Furthermore, the high dependence of spinal cord MNs on CMA activity may underlie their selective vulnerability to degeneration when CMA is impaired, and highlight CMA enhancement as a promising therapeutic strategy to restore proteostasis and prevent MN degeneration in ALS.

2026-05-05T18:48:02Z Garcia-Lopez, Raquel Pombero, Ana Estirado, Alicia Geijo-Barrientos, Emilio Martinez, Salvador https://hdl.handle.net/11000/39845 2026-05-06T01:06:41Z 2026-05-05T18:45:38Z

Título : Interneuron Heterotopia in the Lis1 Mutant Mouse Cortex Underlies a Structural and Functional Schizophrenia-Like Phenotype Autor : Garcia-Lopez, Raquel; Pombero, Ana; Estirado, Alicia; Geijo-Barrientos, Emilio; Martinez, Salvador Resumen : LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.

2026-05-05T18:45:38Z Domínguez-Sala, Eduardo Valdés-Sánchez, L Canals, V Reiner, O Pombero, Ana García-López, R Estirado, A Pastor, D Geijo-Barrientos, E Martínez, S https://hdl.handle.net/11000/39844 2026-05-06T01:06:40Z 2026-05-05T18:43:45Z

Título : Abnormalities in Cortical GABAergic Interneurons of the Primary Motor Cortex Caused by Lis1 (Pafah1b1) Mutation Produce a Non-drastic Functional Phenotype Autor : Domínguez-Sala, Eduardo; Valdés-Sánchez, L; Canals, V; Reiner, O; Pombero, Ana; García-López, R; Estirado, A; Pastor, D; Geijo-Barrientos, E; Martínez, S Resumen : LIS1 (PAFAH1B1) plays a major role in the developing cerebral cortex, and haploinsufficient mutations cause human lissencephaly type 1. We have studied morphological and functional properties of the cerebral cortex of mutant mice harboring a deletion in the first exon of the mouse Lis1 (Pafah1b1) gene, which encodes for the LisH domain. The Lis1/sLis1 animals had an overall unaltered cortical structure but showed an abnormal distribution of cortical GABAergic interneurons (those expressing calbindin, calretinin, or parvalbumin), which mainly accumulated in the deep neocortical layers. Interestingly, the study of the oscillatory activity revealed an apparent inability of the cortical circuits to produce correct activity patterns. Moreover, the fast spiking (FS) inhibitory GABAergic interneurons exhibited several abnormalities regarding the size of the action potentials, the threshold for spike firing, the time course of the action potential after-hyperpolarization (AHP), the firing frequency, and the frequency and peak amplitude of spontaneous excitatory postsynaptic currents (sEPSC's). These morphological and functional alterations in the cortical inhibitory system characterize the Lis1/sLis1 mouse as a model of mild lissencephaly, showing a phenotype less drastic than the typical phenotype attributed to classical lissencephaly. Therefore, the results described in the present manuscript corroborate the idea that mutations in some regions of the Lis1 gene can produce phenotypes more similar to those typically described in schizophrenic and autistic patients and animal models.

2026-05-05T18:43:45Z Ochando, Isabel Jover-Gil, Sara Ripoll, Juan-José Candela, Héctor Vera, Antonio Ponce, María Rosa Martínez-Laborda, Antonio Micol, José Luis https://hdl.handle.net/11000/39241 2026-02-13T02:09:50Z 2026-02-12T15:02:12Z

Título : Mutations in the microRNA complementarity site of the INCURVATA4 gene perturb meristem function and adaxialize lateral organs in arabidopsis Autor : Ochando, Isabel; Jover-Gil, Sara; Ripoll, Juan-José; Candela, Héctor; Vera, Antonio; Ponce, María Rosa; Martínez-Laborda, Antonio; Micol, José Luis Resumen : Here, we describe how the semidominant, gain-of-function icu4-1 and icu4-2 alleles of the INCURVATA4 (ICU4) gene alter leaf phyllotaxis and cell organization in the root apical meristem, reduce root length, and cause xylem overgrowth in the stem. The ICU4 gene was positionally cloned and found to encode the ATHB15 transcription factor, a class III homeodomain/leucine zipper family member, recently named CORONA. The icu4-1 and icu4-2 alleles bear the same point mutation that affects the microRNA complementarity site of ICU4 and is identical to those of several semidominant alleles of the class III homeodomain/leucine zipper family members PHABULOSA and PHAVOLUTA. The icu4-1 and icu4-2 mutations significantly increase leaf transcript levels of the ICU4 gene. The null hst-1 allele of the HASTY gene, which encodes a nucleocytoplasmic transporter, synergistically interacts with icu4-1, the double mutant displaying partial adaxialization of rosette leaves and carpels. Our results suggest that the ICU4 gene has an adaxializing function and that it is down-regulated by microRNAs that require the HASTY protein for their biogenesis.

2026-02-12T15:02:12Z Alonso-Cantabrana, Hugo Ripoll, Juan José Ochando, Isabel Vera, Antonio Ferrándiz, Cristina Martínez-Laborda, Antonio https://hdl.handle.net/11000/39240 2026-02-13T02:09:50Z 2026-02-12T14:55:57Z

Título : Common regulatory networks in leaf and fruit patterning revealed by mutations in the Arabidopsis ASYMMETRIC LEAVES1 gene Autor : Alonso-Cantabrana, Hugo; Ripoll, Juan José; Ochando, Isabel; Vera, Antonio; Ferrándiz, Cristina; Martínez-Laborda, Antonio Resumen : Carpels and leaves are evolutionarily related organs, as the former are thought to be modified leaves. Therefore, developmental pathways that play crucial roles in patterning both organs are presumably conserved. In leaf primordia of Arabidopsis thaliana, the ASYMMETRIC LEAVES1 (AS1) gene interacts with AS2 to repress the class I KNOTTED1-like homeobox (KNOX) genes BREVIPEDICELLUS (BP), KNAT2 and KNAT6, restricting the expression of these genes to the meristem. In this report, we describe how AS1, presumably in collaboration with AS2, patterns the Arabidopsis gynoecium by repressing BP, which is expressed in the replum and valve margin, interacts in the replum with REPLUMLESS (RPL), an essential gene for replum development, and positively regulates the expression of this gene. Misexpression of BP in the gynoecium causes an increase in replum size, while the valve width is slightly reduced, and enhances the effect of mutations in FRUITFULL (FUL), a gene with an important function in valve development. Altogether, these findings strongly suggest that BP plays a crucial role in replum development. We propose a model for pattern formation along the mediolateral axis of the ovary, whereby three domains (replum, valve margin and valve) are specified by the opposing gradients of two antagonistic factors, valve factors and replum factors, the class I KNOX genes working as the latter.

2026-02-12T14:55:57Z Ochando, Isabel Urbano, Antonio Rubio, Juana Rueda, Joaquin https://hdl.handle.net/11000/39239 2026-02-13T02:09:39Z 2026-02-12T14:48:43Z

Título : Clinical and molecular characterization of a patient with a combination of a deletion and a duplication of 22q13 using array CGH Autor : Ochando, Isabel; Urbano, Antonio; Rubio, Juana; Rueda, Joaquin Resumen : Phelan-McDermid syndrome is caused by the loss of terminal regions of different sizes at 22q13. There is a wide range of severity of symptoms in patients with a 22q13 deletion, but these patients usually show neonatal hypotonia, global developmental delay, and dysmorphic traits. We carried out a clinical and molecular characterization of a patient with neonatal hypotonia and dysmorphic features. Array-based comparative genomic hybridization showed an 8.24 Mb terminal deletion associated with a 0.20 Mb duplication. Characterization of patients with Phelan-McDermid syndrome both clinically and at the molecular level allows genotype-phenotype correlations that provide clues to help elucidate the clinical implications.

2026-02-12T14:48:43Z Ochando, Isabel Gonzalez-Reig, Santiago Ripoll, Juan José Vera, Antonio Martínez-Laborda, Antonio https://hdl.handle.net/11000/39238 2026-02-13T02:09:35Z 2026-02-12T14:42:48Z

Título : Alteration of the shoot radial pattern in Arabidopsis thaliana by a gain-of-function allele of the class III HD-Zip gene INCURVATA4 Autor : Ochando, Isabel; Gonzalez-Reig, Santiago; Ripoll, Juan José; Vera, Antonio; Martínez-Laborda, Antonio Resumen : Class III HD-Zip (HD-Zip III) family genes play key roles in a number of fundamental developmental programs in Arabidopsis thaliana, such as embryo patterning, meristem initiation and homeostasis, lateral organ polarity and vascular development. Semidominant gain-of-function alleles of the HD-Zip III genes PHABULOSA (PHB), PHAVOLUTA (PHV) and REVOLUTA (REV) disrupt the negative regulation of these genes by a mechanism of microRNA interference. We provide evidence that the gain-of-function icu4-1 allele of INCURVATA4, a gene encoding the HD-Zip III transcription factor ATHB15/CORONA (CNA), stimulates the production of vascular tissues, supporting a role for ICU4 in promoting vascular development. Occasionally, homozygous mutants for this allele show a reduced number of thick shoot vascular bundles, although normal collateral polarity remains unchanged. Genetic analysis of icu4-1 and phb-1D, a gain-of-function allele of the related PHB gene, revealed antagonism in lateral organ polarity between both mutations and a synergistic interaction in shoots, with transformation of the polarized collateral bundles into a radialized amphivasal pattern. These results indicate that the precise regulation of HD-Zip III genes confers positional information which is required to establish the number and pattern of vascular bundles in the stem. In addition, we present results that suggest an interaction between ICU4 function and auxin signaling.

2026-02-12T14:42:48Z Choi, Yeon Ja Laclef, Christine Yang, Ning Andreu-Cervera, Abraham Lewis, Joshua Mao, Xuming LI, LI Snedecor, Elizabeth R. Takemaru, Ken-Ichi Quin, Chuan Schneider-Maunoury, Sylvie Shroyer, Kenneth Hannun, yusuf Koch, Peter J Clark, Richard https://hdl.handle.net/11000/39118 2026-02-06T02:05:54Z 2026-02-05T09:12:04Z

Título : RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis Autor : Choi, Yeon Ja; Laclef, Christine; Yang, Ning; Andreu-Cervera, Abraham; Lewis, Joshua; Mao, Xuming; LI, LI; Snedecor, Elizabeth R.; Takemaru, Ken-Ichi; Quin, Chuan; Schneider-Maunoury, Sylvie; Shroyer, Kenneth; Hannun, yusuf; Koch, Peter J; Clark, Richard Resumen : Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the Rpgrip1l gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway.

2026-02-05T09:12:04Z Andreu-Cervera, Abraham Anselme, Isabelle Karam, Alice Laclef, Christine Catala, Martín Schneider-Maunoury, Sylvie https://hdl.handle.net/11000/39117 2026-02-06T02:05:52Z 2026-02-05T09:11:21Z

Título : The Ciliopathy Gene Ftm/Rpgrip1l Controls Mouse Forebrain Patterning via Region-Specific Modulation of Hedgehog/Gli Signaling Autor : Andreu-Cervera, Abraham; Anselme, Isabelle; Karam, Alice; Laclef, Christine; Catala, Martín; Schneider-Maunoury, Sylvie Resumen : Primary cilia are essential for CNS development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rpgrip1l ciliopathy gene is disrupted. At the end of gestation, Ftm-/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm-/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. In Ftm-/- embryos, Sonic hedgehog (Shh) expression was virtually lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. Gli activity was severely downregulated but not lost in the ventral forebrain and in regions adjacent to the Shh-expressing ZLI. Reintroduction of the repressor form of Gli3 into the Ftm-/- background restored optic cup formation. Our data thus uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.

2026-02-05T09:11:21Z