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1.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474321

RESUMO

The appropriate expression and localization of cell surface cell adhesion molecules must be tightly regulated for optimal synaptic growth and function. How neuronal plasma membrane proteins, including cell adhesion molecules, cycle between early endosomes and the plasma membrane is poorly understood. Here we show that the Drosophila homolog of the chromatin remodeling enzymes CHD7 and CHD8, Kismet, represses the synaptic levels of several cell adhesion molecules. Neuroligins 1 and 3 and the integrins αPS2 and ßPS are increased at kismet mutant synapses but Kismet only directly regulates transcription of neuroligin 2. Kismet may therefore regulate synaptic CAMs indirectly by activating transcription of gene products that promote intracellular vesicle trafficking including endophilin B (endoB) and/or rab11. Knock down of EndoB in all tissues or neurons increases synaptic FasII while knock down of EndoB in kis mutants does not produce an additive increase in FasII. In contrast, neuronal expression of Rab11, which is deficient in kis mutants, leads to a further increase in synaptic FasII in kis mutants. These data support the hypothesis that Kis influences the synaptic localization of FasII by promoting intracellular vesicle trafficking through the early endosome.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Junção Neuromuscular/metabolismo , Sinapses/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Neurônios/metabolismo
2.
Sci Rep ; 9(1): 19368, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852969

RESUMO

Chromatin remodeling proteins of the chromodomain DNA-binding protein family, CHD7 and CHD8, mediate early neurodevelopmental events including neural migration and differentiation. As such, mutations in either protein can lead to neurodevelopmental disorders. How chromatin remodeling proteins influence the activity of mature synapses, however, is relatively unexplored. A critical feature of mature neurons is well-regulated endocytosis, which is vital for synaptic function to recycle membrane and synaptic proteins enabling the continued release of synaptic vesicles. Here we show that Kismet, the Drosophila homolog of CHD7 and CHD8, regulates endocytosis. Kismet positively influenced transcript levels and bound to dap160 and endophilin B transcription start sites and promoters in whole nervous systems and influenced the synaptic localization of Dynamin/Shibire. In addition, kismet mutants exhibit reduced VGLUT, a synaptic vesicle marker, at stimulated but not resting synapses and reduced levels of synaptic Rab11. Endocytosis is restored at kismet mutant synapses by pharmacologically inhibiting the function of histone deacetyltransferases (HDACs). These data suggest that HDAC activity may oppose Kismet to promote synaptic vesicle endocytosis. A deeper understanding of how CHD proteins regulate the function of mature neurons will help better understand neurodevelopmental disorders.


Assuntos
Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Proteínas de Drosophila/genética , Endocitose/genética , Proteínas de Homeodomínio/genética , Vesículas Sinápticas/genética , Aciltransferases/genética , Animais , Proteínas de Ligação a DNA/genética , Drosophila melanogaster/genética , Histona Desacetilase 1/genética , Humanos , Neurônios/metabolismo , Vesículas Sinápticas/metabolismo , Fatores de Transcrição/genética , Sítio de Iniciação de Transcrição/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Glutamato/genética , Proteínas de Transporte Vesicular/genética , Proteínas rab de Ligação ao GTP/genética
3.
Dev Neurobiol ; 79(8): 805-818, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31581354

RESUMO

The Class I basic helix-loop-helix (bHLH) proteins are highly conserved transcription factors that are ubiquitously expressed. A wealth of literature on Class I bHLH proteins has shown that these proteins must homodimerize or heterodimerize with tissue-specific HLH proteins in order to bind DNA at E-box consensus sequences to control tissue-specific transcription. Due to its ubiquitous expression, Class I bHLH proteins are also extensively regulated posttranslationally, mostly through dimerization. Previously, we reported that in addition to its role in promoting neurogenesis, the Class I bHLH protein daughterless also functions in mature neurons to restrict axon branching and synapse number. Here, we show that part of the molecular logic that specifies how daughterless functions in neurogenesis is also conserved in neurons. We show that the Type V HLH protein extramacrochaetae (Emc) binds to and represses daughterless function by sequestering daughterless to the cytoplasm. This work provides initial insights into the mechanisms underlying the function of daughterless and Emc in neurons while providing a novel understanding of how Emc functions to restrict daughterless activity within the cell.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Citoplasma/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Neurônios/metabolismo , Proteínas Repressoras/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Neurogênese/fisiologia , Terminações Pré-Sinápticas/metabolismo , Proteínas Repressoras/genética
4.
iScience ; 16: 79-93, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31153043

RESUMO

Axon pruning is critical for sculpting precise neural circuits. Although axon pruning has been described in the literature for decades, relatively little is known about the molecular and cellular mechanisms that govern axon pruning in vivo. Here, we show that the epigenetic reader Kismet (Kis) is required for developmental axon pruning in Drosophila mushroom bodies. Kis binds to cis-regulatory elements of the steroid hormone receptor ecdysone receptor (ecr) gene and is necessary for activating expression of EcR-B1. Kis promotes the active H3K36 di- and tri-methylation and H4K16 acetylation histone marks at the ecr locus. We show that transgenic EcR-B1 can rescue axon pruning and memory defects associated with loss of Kis and that the histone deacetylase inhibitor SAHA also rescues these phenotypes. EcR protein abundance is the cell-autonomous, rate-limiting step required to initiate axon pruning in Drosophila, and our data suggest this step is under the epigenetic control of Kis.

5.
Mol Cell Neurosci ; 87: 77-85, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29249293

RESUMO

We are beginning to appreciate the complex mechanisms by which epigenetic proteins control chromatin dynamics to tightly regulate normal development. However, the interaction between these proteins, particularly in the context of neuronal function, remains poorly understood. Here, we demonstrate that the activity of histone deacetylases (HDACs) opposes that of a chromatin remodeling enzyme at the Drosophila neuromuscular junction (NMJ). Pharmacological inhibition of HDAC function reverses loss of function phenotypes associated with Kismet, a chromodomain helicase DNA-binding (CHD) protein. Inhibition of HDACs suppresses motor deficits, overgrowth of the NMJ, and defective neurotransmission associated with loss of Kismet. We hypothesize that Kismet and HDACs may converge on a similar set of target genes in the nervous system. Our results provide further understanding into the complex interactions between epigenetic protein function in vivo.


Assuntos
DNA Helicases/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Cromatina , DNA Helicases/genética , Histona Desacetilases/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Junção Neuromuscular/genética , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/genética
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