RESUMO
The tumor suppressor vitamin D(3) up-regulated protein 1 (VDUP1) is expressed throughout the developing and mature Drosophila nervous system, but its regulatory pathways are not well understood. Within the developing Drosophila visual system, down-regulation of VDUP1 in lamina precursor cells (LPCs) coincided with the arrival of retinal axons into the lamina target field, suggesting VDUP1 regulation by an axonally transmitted signal. Hedgehog (Hh) is a signal well known to coordinate LPC proliferation and differentiation in response to retinal axon innervation, and analysis of orthologous dvdup1 promoters identified an evolutionarily conserved binding site for the Hh-dependent transcription factor cubitus interruptus (Ci). Hh-dependent regulation of VDUP1 in the developing lamina was confirmed in Hh loss-of-function backgrounds where VDUP1 expression was maintained in LPCs, inhibiting both cell proliferation and lamina neurogenesis. This putative coupling of VDUP1 to the Hh signaling pathway may provide novel insights into the mechanisms controlling brain growth and development.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas Hedgehog/metabolismo , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células , Olho Composto de Artrópodes/crescimento & desenvolvimento , Olho Composto de Artrópodes/fisiologia , Sequência Conservada , Regulação para Baixo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Modelos Neurológicos , Dados de Sequência Molecular , Neurogênese/fisiologia , Neurônios/fisiologia , Lobo Óptico de Animais não Mamíferos/crescimento & desenvolvimento , Lobo Óptico de Animais não Mamíferos/fisiologia , Neurônios Retinianos/fisiologia , Células-Tronco/fisiologia , Vias Visuais/crescimento & desenvolvimento , Vias Visuais/fisiologiaRESUMO
The tumor suppressor, vitamin D(3) up-regulated protein 1 (VDUP1), regulates cell cycle progression by suppressing AP-1-dependent transcription. Loss of VDUP1 activity is associated with tumorigenesis but little is known about VDUP1 regulatory controls or developmental roles. Here we show that the Drosophila homolog of human VDUP1 (dVDUP1) is expressed throughout the nervous system at all stages of development, the first in vivo analysis of VDUP1 expression patterns in the brain. During neurogenesis dVDUP1 expression is transiently down-regulated coincident with neuroblast delamination. Subsequent to expression of the neuronal marker elav, dVDUP1 is up-regulated to varying degrees in developing neurons. In contrast, dVDUP1 expression is both robust and sustained during gliogenesis, and the cis-regulatory region of the dvdup1 gene contains consensus binding sites for the glial fate gene reversed polarity (repo). Expression of dVDUP1 in presumptive glia is lost in embryos deficient for the glial fate genes glial cells missing (gcm) and repo. Conversely, ectopic expression of gcm or repo was sufficient to induce dVDUP1 expression in the nervous system. Taken together, these data suggest a novel role for the dVDUP1 tumor suppressor during nervous system development as a regulatory target for REPO during gliogenesis.