Abstract
Duchenne Muscular Dystrophy, a genetic disorder that results in a gradual breakdown of muscle, is associated to mild to severe cognitive impairment in about one-third of dystrophic patients. The brain dysfunction is independent of the muscular pathology, occurs early, and is most likely due to defects in the assembly of the Dystrophin-associated Protein Complex (DPC) during embryogenesis. We have recently described the interaction of the DPC component β-dystrobrevin with members of complexes that regulate chromatin dynamics, and suggested that β-dystrobrevin may play a role in the initiation of neuronal differentiation. Since oxygen concentrations and miRNAs appear as well to be involved in the cellular processes related to neuronal development, we have studied how these factors act on β-dystrobrevin and investigated the possibility of their functional interplay using the NTera-2 cell line, a well-established model for studying neurogenesis. We followed the pattern of expression and regulation of β-dystrobrevin during the early stages of neuronal differentiation induced by exposure to retinoic acid (RA) under hypoxia as compared with normoxia, and found that β-dystrobrevin expression is regulated during RA-induced differentiation of NTera-2 cells. We also found that β-dystrobrevin pattern is delayed under hypoxic conditions, together with a delay in the differentiation and an increase in the proliferation rate of cells. We identified miRNA-143 as a direct regulator of β-dystrobrevin expression, demonstrated that β-dystrobrevin is expressed in the nucleus and showed that, in line with our previous in vitro results, β-dystrobrevin is a repressor of synapsin I in live cells. Altogether the newly identified regulatory pathway miR-143/β-dystrobrevin/synapsin I provides novel insights into the functions of β-dystrobrevin and opens up new perspectives for elucidating the molecular mechanisms underlying the neuronal involvement in muscular dystrophy.
Highlights
The dystrophin-related and associated protein dystrobrevin is a cytoplasmic component of the dystrophin-associated protein complex (DPC), a membrane complex that serves both structural and signaling functions [1,2] in muscle and non-muscle tissues
We verified the effect of hypoxia on these cells by following hypoxia-inducible factors (HIFs)-1α nuclear activation through Western blot on NTera-2 cl. D1 (NT2/D1) nuclear extracts, and found that HIF-1α translocated into the nucleus in hypoxia (Fig 1A) but not in normoxia, as expected [44]
Aiming at shedding light on the neuronal involvement in Duchenne muscular dystrophy (DMD), we have here investigated the possibility of a functional role of β-dystrobrevin in the molecular mechanisms underlying the first steps of neural differentiation
Summary
The dystrophin-related and associated protein dystrobrevin is a cytoplasmic component of the dystrophin-associated protein complex (DPC), a membrane complex that serves both structural and signaling functions [1,2] in muscle and non-muscle tissues. Α-Dystrobrevin is expressed predominantly in muscle and brain whereas β-dystrobrevin is expressed in non-muscle tissues such as brain, kidney, lung and liver [9] Their cellular functions are beginning to be elucidated through the study of their associated proteins, the exact role of dystrobrevins remains unclear. Mice lacking α-dystrobrevin exhibit a mild muscular dystrophy but no obvious central nervous system (CNS) defects [10], and mice lacking β-dystrobrevin are outwardly normal [11]; interestingly, double knock-out mice lacking both α- and β-dystrobrevin have a mild myopathy plus synaptic defects and abnormal motor behavior [12] This provides evidence that DPC components other than dystrophin influence the synaptic structure in certain areas of the brain, and suggests that motor deficits in dystrophic patients may reveal peripheral and CNS defects [12]. These interactions suggest that in neurons dystrobrevin may have a role in the early processes of differentiation [20], opening a new scenario that would help in understanding the molecular mechanisms underlying the neuronal involvement in DMD
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