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[eng] Neuroinflammation is present in practically all neurological disorders. Microglial cells, the main representatives of the endogenous immune system of the brain, play a key role in neuroinflammation, although peripheral immune cells can also be involved. In the last years, a considerable effort has been focused on the study of the modulation of the inflammatory response as a possible therapeutic strategy in neurological diseases. Parkinson’s disease (PD) is the second most common neurodegenerative disease and is mainly characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and an abnormal intracellular accumulation of α-synuclein protein, known as Lewy bodies. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. Activated microglia has been described in the post-mortem brains of PD patients; however, the pathogenic role of the immune system in PD remains enigmatic. In the present thesis, we have studied one of the inhibitory mechanisms suggested to be involved in the control of the inflammatory response in microglial cells: CD200 ligand (mainly expressed in neurons and astrocytes) - CD200R1 receptor (mainly microglial) interaction. The aim of this thesis was to study the involvement of the microglial inhibitory immune receptor CD200R1 in the modulation of neuroinflammation and its potential as therapeutic target in PD. In vitro, the disruption of the CD200-CD200R1 system potentiated the pro-inflammatory response of glial cells. Mesencephalic cultures from CD200-deficient mice showed a higher microglial proportion and increased sensitivity of dopaminergic neurons to the neurotoxin 1-methyl-4- phenylpyridinium (MPP+). The parkinsonian neurotoxins MPP+ and rotenone impaired the immune response of glial cells to pro- and anti-inflammatory stimuli and changed CD200 and CD200R1 expression. In vivo, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) experimental mouse model of PD dopaminergic neurodegeneration and glial activation were associated to changes in CD200 and CD200R1 expression: mainly a transient increase in striatal CD200R1 and a sustained decrease in CD200full in the ventral midbrain. When we potentiated the CD200-CD200R1 system by administering a CD200R1 agonist, we observed partial protection in dopaminergic neurons of the SNpc, which was accompanied by an attenuated microglial activation. On the contrary, CD200-deficient mice showed a more reactive microglial phenotype at early stages after MPTP administration, although it was not associated to an exacerbated neurodegeneration. Post-mortem brain samples from substantia nigra, frontal cortex and hippocampus of PD patients had particular changes in the expression of the mRNA variants and protein isoforms of the CD200-CD200R1 system. In conclusion, these results suggest that the CD200-CD200R1 system is a potential target to control microglial activation in PD, and that the mechanisms of control of microglial activation may be used to modulate microglial activation and its potential neurotoxicity on neurodegenerative diseases., [spa] La neuroinflamació està present en pràcticament tots els desordres neurològics i la micròglia hi juga un paper clau. La malaltia de Parkinson (MP) és la segona malaltia neurodegenerativa més comú i està caracteritzada per la pèrdua de neurones dopaminèrgiques de la part compacta de la substancia negra (SNpc) i la presència de cossos de Lewy. Hi ha evidència de que la neurodegeneració dopaminèrgica està influenciada pel sistema immunitari innat. En aquesta tesi, hem estudiat un dels mecanismes inhibitoris suggerits d’estar involucrats en el control de la resposta inflamatòria de la micròglia: el lligand CD200 (principalment neuronal i astrocític) i el receptor CD200R1 (principalment microglial). La finalitat era estudiar el rol de CD200R1 en la modulació de la neuroinflamació i el seu potencial com a diana terapèutica en la MP. In vitro, la disrupció del sistema CD200-CD200R1 va potenciar la resposta pro-inflamatòria glial. Cultius mesencefàlics de ratolins deficients en CD200 van mostra una major proporció de micròglia i una sensibilitat incrementada de les neurones dopaminèrgiques al 1-metil-4- fenilpiridina (MPP+). Les neurotoxines parkinsonianes MPP+ i rotenona van alterar la resposta glial a estímuls inflamatoris i van modificar l’expressió de CD200 i CD200R1. In vivo, en el model de ratolí de la MP amb 1-metil-4-fenil,6-tetrahidropiridina (MPTP) la mort dopaminèrgica i l’activació glial es van associar a un increment transitori de CD200R1 estriatal i una disminució sostinguda de CD200full en el mesencèfal ventral. L’administració d’un agonista de CD200R1 va protegir parcialment les neurones dopaminèrgiques de la SNpc i va atenuar l’activació microglial. Contràriament, ratolins deficients en CD200 van mostrar un fenotip microglial més reactiu en estadis inicials després de l’administració del MPTP, encara que no es va associar a una neurodegeneració exacerbada. A mostres de cervell post-mortem de la SN, còrtex frontal i hipocamp de pacients amb MP es van observar canvis en l’expressió de les variants de RNA i les isoformes proteiques del sistema CD200-CD200R1. En conclusió, aquests resultats suggereixen que el sistema CD200-CD200R1 és una diana potencial pel control de l’activació microglial en la MP, i que els mecanismes de control de l’activació microglial podrien ser usats per modular l’activació microglial i el seu potencial neurotòxic en les malalties neurodegeneratives.

β-Catenin, the core element of the Wnt/β-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/β-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a ‘whole animal’ developmental framework to approach this question. Here we identify a C-terminally truncated β-catenin (β-catenin4), generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of β-catenin4 is to modulate the activity of β-catenin1, the planarian β-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of β-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear β-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of β-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/β-catenin signaling in specific cellular contexts., Author summary The Wnt signaling pathway is essential for proper intercellular communication in every developmental process since it controls basic cellular events as cell fate or proliferation. The key element of the Wnt signaling is β-catenin, which controls the transcription of multiple genes in the Wnt receiving cell. A main level of regulation of the Wnt/β-catenin signaling occurs in the cytoplasm, where β-catenin protein levels depend on the activity of the β-catenin destruction complex. However, once it reaches the nucleus, β-catenin transcriptional activity requires a fine-tuned regulation to enable the multiple context-specific responses that it performs. These nuclear mechanisms that regulate the Wnt/β-catenin signaling remain poorly understood. Here we report the existence of C-terminal truncated forms of β-catenin in planarians (β-cat3 and 4), which, in vitro, do not show transactivation activity and compete with the canonical planarian β-catenin (β-cat1), thus acting as competitor inhibitors. Functional analyses in planarians indicate that β-cat4 acts as a negative regulator of β-cat1 during planarian eye photoreceptor specification. We provide evidence to suggest that this novel mechanism for the regulation of nuclear β-catenin activity could be conserved across animal evolution.