RESUMO
High mobility group (HMG) proteins concentrate in the nucleus, interacting with chromatin. Amphoterin is an HMG protein (HMGB1) that has been shown to have extranuclear functions and can be secreted from some cell types. Exogenous amphoterin can increase neurite growth, suggesting that the secreted protein may have growth promoting activities in neurons. Consistent with this, we show that depletion of amphoterin mRNA from cultured adult rat DRG neurons attenuates neurite outgrowth, pointing to autocrine or paracrine mechanisms for its growth-promoting effects. The mRNA encoding amphoterin localizes to axonal processes and we showed recently that its 3'-UTR is sufficient for axonal localization of heterologous transcripts (Donnelly et al., 2013). Here, we show that amphoterin mRNA is transported constitutively into axons of adult DRG neurons. A preconditioning nerve injury increases the levels of amphoterin protein in axons without a corresponding increase in amphoterin mRNA in the axons. A 60 nucleotide region of the amphoterin mRNA 3'-UTR is necessary and sufficient for its localization into axons of cultured sensory neurons. Amphoterin mRNA 3'-UTR is also sufficient for axonal localization in distal axons of DRG neurons in vivo. Overexpression of axonally targeted amphoterin mRNA increases axon outgrowth in cultured sensory neurons, but axon growth is not affected when the overexpressed mRNA is restricted to the cell body.
Assuntos
Axônios/metabolismo , Regulação da Expressão Gênica/genética , Proteína HMGB1/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Células Receptoras Sensoriais/citologia , Regiões 3' não Traduzidas/genética , Animais , Axônios/efeitos dos fármacos , Transporte Biológico/genética , Células Cultivadas , Gânglios Espinais/citologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteína HMGB1/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fotodegradação , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução GenéticaRESUMO
PURPOSE: Considering the paucity of reports on large series of patients with tibial hemimelia, we assessed the clinical spectrum of this rare congenital disorder in patients seen at a single Indian center over 10 years. METHODS: Retrospective review of medical records of patients seen at single center in 10 years. RESULTS: Thirty-five cases of TH, mostly Jones types Ia (18) and II (10), were diagnosed in 24 patients (13 had unilateral TH). Associated foot deformities included equinovarus (22), varus foot (10), absence of the medial row of toes (5) and polydactyly (3). Upper limbs anomalies included split-hand deformity (five patients) and radial club hand (two patients). Nine limbs of seven patients were surgically reconstructed. Modified orthosis was provided to seven patients, custom designed prosthesis fitment in six and amputation with prosthesis fitment in one. Patients presenting at adolescence or later were habituated to their deformity for indoor ambulation; families declined amputation. CONCLUSION: Reports of more TH cases will provide input to researchers to consider comprehensive rehabilitation for enhancing indoor and community ambulation.