RESUMO
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
Assuntos
Processamento Alternativo , Éxons , Neurônios , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Proteínas Serina-Treonina Quinases , Animais , Humanos , Camundongos , Éxons/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Fosforilação , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
The bariatric surgery techniques applied in patients with obesity have reported a great ability to improve Type 2 Diabetes mellitus (T2DM). Some published data report an increasing betacell mass in some surgical processes. This mechanism was specially seen in the bariatric surgeries which affect the length of the small bowel. The intrinsic mechanism that links both phenomena seemed to be related to the enterohormonal secretion pattern. Many enteral hormones have been invoked as the effector of these mechanisms. Previous reports focused on the medial portion of jejunum, as the precise place in which some particular enterohormones determine the homeostatic glycemic improvement. Goto-Kakizaki diabetic male rats underwent surgery to exclude the 50% medial jejunum from the normal nutrients flow. This medial portion of jejunum was not resected, but anastomosed by both extremes to the abdominal wall, and a stoma was performed. This surgery wasnamed as Medial Jejunal Exclusion (MJE). We studied the functional parameters in a three-month survival period. In this sense basal glycaemia, weight increase and food intake were not modified between the surgical and control groups. The study presented a mortality of the 24%. This model was designed for the late study of serum and enterohormones release in this jejunal portion, excluded of nutrients flow. We report a new surgical technique, which appears to balance the homeostatic processes in order to maintain the survival of diabetic rats. Thus, this mechanism could be in the basis of T2DM improvement, and this novel surgical model will help study this precise portion of jejunum
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Assuntos
Animais , Masculino , Ratos , Jejuno/cirurgia , Cirurgia Bariátrica/métodos , Diabetes Mellitus Tipo 2 , Diabetes Mellitus Experimental , Fatores de Tempo , Modelos AnimaisRESUMO
Se presenta un estudio multidisciplinario y multicéntrico llevado a cabo durante el período 1988 - 2003 por investigadores de 10 instituciones venezolanas con la finalidad de aportar nuevos datos sobre la situación epidemiológica de la enfermedad de Chagas en el país. El artículo incluye información basada en la detección de la infección por Trypanosoma cruzi en pacientes referidos a un centro diagnóstico y en individuos muestreados en localidades rurales de diferentes regiones de Venezuela. En el primer grupo de 310 pacientes examinados, 168 (54.2 por ciento) resultaron sero-positivos a T. cruzi; 75 (44.6 por ciento) en la fase aguda, con 52 de ellos (69.3 por ciento) mostrando parasitemia patente, de los cuales 36 por ciento eran niños entre 0 y 10 años. El restante número de infectados arrojó el 43.5 por ciento (73/168) en la fase crónica, con diferentes grados de afección cardiaca, y un 11.9 por ciento (20/168) de individuos asintomáticos con infecciones inaparentes u ocultas. Asimismo, exámenes serológicos realizados en 3.993 individuos de 75 localidades rurales de 11 estados de Venezuela, revelaron un 11.2 por ciento de seroprevalencia a T.cruzi, detectándose, del total de individuos seropositivos, el 8.5 por ciento (38/448) de infecciones en infantes menores de 10 años de edad. Se informa sobre factores de riesgo de transmisión chagásica considerando la frecuencia de infestación por especies triatominas en palmeras disecadas, la estimación de la domiciliación triatomínica en la vivienda rural y la frecuencia de picadura en moradores de las áreas endémicas estudiadas. Se concluye que la enfermedad de Chagas podría estar re-emergiendo en Venezuela a juzgar por la activa transmisión detectada durante la última década. Se considera el éxito de la campaña anti-chagásica durante los últimos 40 años y se evalúa en el marco de los presentes resultados. La situación epidemiológica de la enfermedad de Chagas en Venezuela es discutida y se sugiere la creación de una política de estado para su control
