RESUMO
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.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Neuroglia/metabolismo , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Linhagem Celular , Colecalciferol/metabolismo , Drosophila/embriologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes de Insetos , Proteínas de Homeodomínio/genética , Humanos , Dados de Sequência Molecular , Mutação , Sistema Nervoso/citologia , Sistema Nervoso/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Ratos , Homologia de Sequência de Aminoácidos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
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
Originally characterized as a cell-cycle inhibitor induced by vitamin D(3), the tumor suppressor vitamin-D(3) upregulated protein 1 (VDUP1) has increasingly been shown to play major physiological roles in cell differentiation and glucose metabolism. Here we show evolutionarily conserved expression patterns of VDUP1 in Drosophila and rat nervous systems, including subcellular localization--cytoplasmic enrichment in neurons and nuclear expression in glia. These anatomical correlates suggested conservation of VDUP1 regulation, which was investigated both functionally and through promoter studies. Characterization of orthologous vdup1 cis-regulatory regions identified evolutionarily conserved sequence blocks (CSBs) with similarities to neural enhancers, including basic helix-loop-helix (bHLH) transcription factor Neurogenin/Math/atonal and Mash/achaete-scute family members. E-boxes (CANNTG), the binding sites for bHLH proteins, were associated with these CSBs as well, including E-boxes known to mediate glucose-dependent upregulation of VDUP1 in nonneuronal cells. Hyperglycemia-induced upregulation of VDUP1 was observed in brain tumor cells and in the Drosophila nervous system, which resulted in developmental arrest. Taken together, these data demonstrate evolutionary conservation of VDUP1 regulation and function, and suggest an expanding role for VDUP1 in nervous system development.