Este trabalho é o primeiro a propor uma função específica para a sinalização pelo AR na ontogenia dos circuitos proprioceptivos e também foi o primeiro a sugerir um papel para a ativação da sinalização pelo AR, via raldh2, na placa do teto da
18 Segundo Carroll et al. (2005) filogenia é o termo comumente utilizado para hipóteses de relações
evolutivas (ou seja, relações filogenéticas) de um grupo de organismos, isto é, determinar as relações ancestrais entre espécies conhecidas (ambas as que vivem e as extintas). Carroll SB, Grenier KJ, Weatherbee DS. From DNA to diversity. Molecular genetics and the evolution of animal design. 2nd ed. New York: Blackwell Publising; 2005.
133 medula espinhal, ainda pouco conhecida. A descrição deste novo domínio de expressão da raldh2 na medula espinhal dorsal representa uma contribuição para o estudo da ontogenia dos circuitos proprioceptivos espinocerebelares e intraespinhais (comissurais), pois nós demonstramos que uma via de sinalização chave, como a sinalização pelo AR, é ativada no contexto específico do desenvolvimento dos interneurônios dorsais 1, que dão origem a esses circuitos. Nossos dados suportam estudos prévios com embriões e células-tronco embrionárias que indicam que a sinalização pelo AR é requerida para a especificação de interneurônios dorsais (Wilson et al., 2004; Murashov et al., 2005). Finalmente, nossos resultados fornecem pistas na fisiopatologia de doenças que causam a perda da propriocepção (como ataxias espinocerebelares), sugerindo que os retinóides podem ser alvos para terapias farmacológicas e para terapias celulares baseadas na diferenciação de células pluripotentes.
134
6 CONCLUSÕES
• O promotor hsp68, apesar de ser bastante utilizado em análises de expressão em embriões de camundongo transgênicos, funciona como um promotor constitutivo quando aplicado na técnica de eletroporação, ativando a expressão do gene-repórter em todas as células eletroporadas. Desta forma, este promotor é inadequado para análise de enhancers em embriões de galinha. Já promotor mínimo do gene da timidina kinase do Herpes Simplex vírus (Tk) é um promotor bastante adequado apara esse tipo de análise.
• Abordagem comparativa é capaz de identificar seqüências regulatórias que desempenham funções conservadas durante o desenvolvimento.
• O enhancer intrônico 1G da raldh2 é um enhancer conservado responsável por ativar a expressão do gene raldh2 na medula espinhal dorsal em tetrápodes.
• O enhancer intrônico 1G é ativado por um mecanismo redundante no qual três elementos cis regulatórios que contém sítios preditos e sobrepostos de ligação para o fator de transcrição relacionado à via de sinalização Wnt, Tfc e para os fatores homeobox tipo caudal ativam o enhancer intrônico 1G na região dorsal da medula espinhal. O padrão de atividade do enhancer intrônico 1G é ainda refinado por dois elementos repressores, um Lim-homeodomínio e um homeobox Tgif, que atuam na região ventral da medula espinhal.
• A expressão do gene raldh2 na medula espinhal dorsal em embriões dos peixes teleósteos medaka e peixe-zebra é ativada por outro módulo regulatório que não o enhancer intrônico 1G.
• O gene raldh2 é expresso transitoriamente em interneurônios dorsais 1 da medula espinhal. Ensaios de hibridação in situ dupla para raldh2 e math1/cath1 (marcadores de interneurônios dorsais 1) nos levaram a descrever este novo território de expressão da raldh2 na medula espinhal. Provavelmente esse domínio
de expressão da raldh2 não foi detectado anteriormente devido ao seu caráter dinâmico.
• Em anfíbios, aves e mamíferos, o enhancer intrônico 1G é responsável pela ativação da sinalização pelo AR em prescursores dos interneurônios dorsais 1, que dão origem à neurônios que conduzem informações proprioceptivas dos membros para o cerebelo e à interneurônios comissurais que coordenam a atividade motora.
• Este trabalho é o primeiro a propor que a sinalização pelo AR está envolvida no desenvolvimento de circuitos proprioceptivos, abrindo a possibilidade do uso de retinóides no estudo de tratamentos de para doenças como ataxias, que levam à perda da propriocepção.
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