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Regulação do Desenvolvimento da Microglia pelo Gene DIA1R: Uma Pista para a Etiologia do Autismo
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As células da microglia são células imunes residentes do sistema nervoso central que desempenham
funções essenciais no desenvolvimento e na homeostasia deste sistema. Nos últimos anos, um número
crescente de estudos sugere que a microglia tem um papel fundamental na patogénese de distúrbios do
desenvolvimento neurológico, tais como as Perturbações do Espectro do Autismo (PEA), tendo sido
proposto que mutações em genes que alterem o número da microglia podem afetar profundamente o neurodesenvolvimento. Neste sentido, a microglia surge como um potencial alvo para o tratamento destes
distúrbios. Contudo, os reguladores moleculares subjacentes ao desenvolvimento da microglia e à
aquisição de suas propriedades funcionais são ainda pouco conhecidos. No passado, a nossa equipa identificou o gene DIA1R (Deleted in Autism 1 Related) como um novo gene implicado em PEA que se encontra altamente expresso nos progenitores hematopoiéticos das células da microglia em embriões de
vertebrados. Neste projeto fomos investigar o papel do gene dia1r no desenvolvimento da microglia do
peixe-zebra. Para tal, quantificamos o número de células da microglia presentes no cérebro de larvas de
peixe-zebra morfantes e mutantes para dia1r utilizando técnicas de citometria de fluxo, coloração com Neutral Red e microscopia confocal. Os nossos resultados demonstraram que o número de microglia é significativamente inferior em larvas morfantes e mutantes para dia1r em relação aos respetivos controlos,
sugerindo que DIA1R promove o desenvolvimento da microglia. Estas evidências apresentam o DIA1R
como um novo regulador da ontogenia da microglia, papel que pode estar subjacente à sua implicação em
PEA. Para além disso, esta investigação contribui para esclarecer o papel etiológico da disfunção da microglia nos distúrbios do desenvolvimento neurológico, trazendo novas perspetivas de diagnóstico e potencial tratamento de subtipos de PEA mediados pela microglia.
Microglia are resident immune cells of the central nervous system that play essential roles in the development and homeostasis of this system. In recent years, a growing body of evidence implicates microglia in the pathogenesis of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). It has been proposed that gene mutations that alter the number of microglia can profoundly affect neurodevelopment. Therefore, microglia has arisen as a novel potential target for the treatment of these disorders. However, little is known about the molecular regulators underlying the development of microglial cells and their acquisition of functional properties. In the past, our team identified DIA1R (Deleted in Autism 1 Related) as a novel gene implicated in ASD that is highly expressed in the hematopoietic progenitors of microglial cells in the vertebrate embryo. In this project, we investigated the role of dia1r in zebrafish microglia development. For this, we quantified the number of microglial cells present in the brain of dia1r morphant and mutant zebrafish larvae using flow cytometry, Neutral Red staining and confocal microscopy. Our results demonstrated that the number of microglia in the brains of dia1r morphant and mutant larvae is significantly lower in comparison to their respective controls, suggesting that DIA1R promotes microglia development. These evidences introduce DIA1R as a novel regulator of microglia ontogeny, a role that may underlie its implication in ASD. In addition, this investigation contributes to clarify the etiological role of microglia disfunction in neurodevelopmental disorders, bringing new perspectives for the diagnosis and potential treatment of microglia-mediated subtypes of ASD.
Microglia are resident immune cells of the central nervous system that play essential roles in the development and homeostasis of this system. In recent years, a growing body of evidence implicates microglia in the pathogenesis of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). It has been proposed that gene mutations that alter the number of microglia can profoundly affect neurodevelopment. Therefore, microglia has arisen as a novel potential target for the treatment of these disorders. However, little is known about the molecular regulators underlying the development of microglial cells and their acquisition of functional properties. In the past, our team identified DIA1R (Deleted in Autism 1 Related) as a novel gene implicated in ASD that is highly expressed in the hematopoietic progenitors of microglial cells in the vertebrate embryo. In this project, we investigated the role of dia1r in zebrafish microglia development. For this, we quantified the number of microglial cells present in the brain of dia1r morphant and mutant zebrafish larvae using flow cytometry, Neutral Red staining and confocal microscopy. Our results demonstrated that the number of microglia in the brains of dia1r morphant and mutant larvae is significantly lower in comparison to their respective controls, suggesting that DIA1R promotes microglia development. These evidences introduce DIA1R as a novel regulator of microglia ontogeny, a role that may underlie its implication in ASD. In addition, this investigation contributes to clarify the etiological role of microglia disfunction in neurodevelopmental disorders, bringing new perspectives for the diagnosis and potential treatment of microglia-mediated subtypes of ASD.
Descrição
Palavras-chave
Desenvolvimento Embrionário Peixe-Zebra Hematopoiese Microglia DIA1R Autismo