RESUMO
Myelin insulates axons in the peripheral nervous system to allow rapid propagation of action potentials, and proper myelination requires the precise regulation of genes encoding myelin proteins, including PMP22. The correct gene dosage of PMP22 is critical; a duplication of PMP22 is the most common cause of the peripheral neuropathy Charcot-Marie-Tooth Disease (CMT) (classified as type 1A), while a deletion of PMP22 leads to another peripheral neuropathy, hereditary neuropathy with liability to pressure palsies. Recently, duplications upstream of PMP22, but not containing the gene itself, were reported in patients with CMT1A like symptoms, suggesting that this region contains regulators of PMP22. Using chromatin immunoprecipitation analysis of two transcription factors known to upregulate PMP22-EGR2 and SOX10-we found several enhancers in this upstream region that contain open chromatin and direct reporter gene expression in tissue culture and in vivo in zebrafish. These studies provide a novel means to identify critical regulatory elements in genes that are required for myelination, and elucidate the functional significance of non-coding genomic rearrangements.
Assuntos
Elementos Facilitadores Genéticos , Proteínas da Mielina/genética , Animais , Sequência de Bases , Linhagem Celular , Cromatina/metabolismo , Sequência Consenso , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Feminino , Genes Reporter , Humanos , Masculino , Camundongos , Proteínas dos Microtúbulos/genética , Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
The transcription factor SOX10 has essential roles in neural crest-derived cell populations, including myelinating Schwann cells-specialized glial cells responsible for ensheathing axons in the peripheral nervous system. Importantly, SOX10 directly regulates the expression of genes essential for proper myelin function. To date, only a handful of SOX10 target loci have been characterized in Schwann cells. Addressing this lack of knowledge will provide a better understanding of Schwann cell biology and candidate loci for relevant diseases such as demyelinating peripheral neuropathies. We have identified a highly-conserved SOX10 binding site within an alternative promoter at the SH3-domain kinase binding protein 1 (Sh3kbp1) locus. The genomic segment identified at Sh3kbp1 binds to SOX10 and displays strong promoter activity in Schwann cells in vitro and in vivo. Mutation of the SOX10 binding site ablates promoter activity, and ectopic expression of SOX10 in SOX10-negative cells promotes the expression of endogenous Sh3kbp1. Combined, these data reveal Sh3kbp1 as a novel target of SOX10 and raise important questions regarding the function of SH3KBP1 isoforms in Schwann cells.
Assuntos
Regulação da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas/genética , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Loci Gênicos , Humanos , Camundongos , Dados de Sequência Molecular , Mutação/genética , Ratos , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/fisiologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologiaRESUMO
BACKGROUND: The management and outcomes of patients receiving nonelective surgical treatment of acute complicated diverticulitis by surgeon specialization have received little attention. METHODS: A retrospective review was performed of consecutive patients with acute complicated diverticulitis who underwent surgery from 2006 to 2013. Patients were analyzed based on surgeon specialty: general surgery (GS) or colorectal surgery (CRS). RESULTS: One hundred fifteen patients met criteria for study; 62 patients in the CRS and 53 in the GS group. GS were more likely to perform Hartmann's procedures or primary anastomosis and less likely to perform primary anastomosis with diverting ileostomy than CRS. There were no differences between groups for any outcome measures on univariate analysis. CRS patients had shorter operative time (P = .001) and length of stay (P ≤ .001) for stoma reversal procedures. Surgeon specialization was not associated with morbidity, readmission, or length of stay on multivariate analysis. CONCLUSIONS: Although surgical management differed significantly between CRS and GS, comparable outcomes were observed at the index hospital admission.