Dp71 gene disruption alters the composition of the dystrophin-associated protein complex and neuronal nitric oxide synthase expression in the hypothalamic supraoptic and paraventricular nuclei

Abstract

DP71 is the major cerebral dystrophin isoform and exerts its multiple functions via the dystrophin-associated protein complex (DAPC), also comprised of β-dystroglycan (β-DG) and α1-syntrophin (α1-Syn). Since DP71 disruption leads to impairment in the central control of the osmoregulatory axis, we investigated: 1) the DAPC composition in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) of Dp71-null mice; and 2) the expression and activity of neuronal nitric oxide synthase (nNOS), because it is a potential partner of the DAPC and a functional index of osmoregulatory axis activity. In wild-type mice, dystrophins and their autosomal homologs the utrophins, β-DG, and α1-Syn were localized in astrocyte end feet. In Dp71-null mice, the levels of β-DG and α1-Syn were lower and utrophin expression did not change. The location of the DAPC in astrocytic end feet suggests that it could be involved in hypothalamic osmosensitivity, which adapts the osmotic response. The altered composition of the DAPC in Dp71-null mice could thus explain why these mice manifest an hypo-osmolar status. In the SON and PVN neurons of Dp71-null mice, nNOS expression and activity were increased. Although we previously established that DP140 is expressedde novoin these neurons, the DAPC remained incomplete due to the low levels of β-DG and α1-Syn produced in these cells. Our data reveal the importance of DP71 for the constitution of a functional DAPC in the hypothalamus. Such DAPC disorganization may lead to modification of the microenvironment of the SON and PVN neurons and thus may result in a perturbed osmoregulation.