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.

DP71 is the major cerebral dystrophin isoform and exerts its multiple functions via the dystrophin-associated protein complex (DAPC), also comprised of ß-dystroglycan (ß-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, ß-DG, and α1-Syn were localized in astrocyte end feet. In Dp71-null mice, the levels of ß-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 expressed de novo in these neurons, the DAPC remained incomplete due to the low levels of ß-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.

A deficit of brain dystrophin 71 impairs hypothalamic osmostat.

Patients with Duchenne muscular dystrophy (DMD) and mdx mice, devoid of dystrophin proteins, show altered ionic homeostasis. To clarify dystrophin's involvement in the central control of osmotic stimuli, we investigated the effect of the disruption of Dp71, the major form of dystrophin in the brain, on the hypothalamoneurohypophysis system (HNHS) osmoregulatory response. Dp71 and Dp140 are the principal DMD gene products in the supraoptic nucleus (SON) and neurohypophysis (NH). They are present in astrocyte and pituicyte end-feet, suggesting involvement in both intrinsic osmosensitivity of the SON and vasopressin (AVP) release from the NH. In Dp71-null mice, the cellular distribution of Dp140 was modified, this protein being detected on the membrane of magnocellular soma. The plasma osmolality of Dp71-null mice was lower than that of wild-type mice under normal conditions, and this difference was maintained after salt loading, indicating a change in the set point for osmoregulation in the absence of Dp71. The increase in AVP levels detected in the SON and NH of the wild-type was not observed in Dp71-null mice following salt loading, and the increase in AVP mRNA levels in the SON was smaller in Dp71-null than in wild-type mice. This suggests that Dp71 may be involved in the functional activity of the HNHS. Its astrocyte end-feet localization emphasizes the importance of neuronal-vascular-glial interactions for the central detection of osmolality. In the SON, Dp71 may be involved in osmosensitivity and definition of the "osmostat," whereas, in the neurohypophysis, it may be involved in fine-tuning AVP release.