Phagophores originate from endoplasmic reticulum membranes in vasopressin neurons in a mouse model of familial neurohypophysial diabetes insipidus

TL;DR

This study shows that phagophores, which help clear cellular waste, originate from endoplasmic reticulum membranes in neurons affected by a genetic disorder in mice.

Contribution

The first in vivo evidence of structural continuity between phagophores and ER membranes in AVP neurons in a mouse model of FNDI.

Findings

Phagophores envelop aggregates within dilated ER in AVP neurons of FNDI mice.

Serial imaging reveals physical connections between phagophores and intact ER membranes.

ER-phagy is induced in AVP neurons under stress conditions like water deprivation.

Abstract

Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) gene. In AVP neurons in a mouse model of FNDI, aggregates of mutant AVP precursors accumulate within a specific compartment of the endoplasmic reticulum (ER). However, as FNDI mice aged, or were exposed to repeated water deprivation, the ER lumen dilated and mutant aggregates dispersed throughout the ER. Meanwhile, autophagic isolation membranes, known as phagophores, emerged to envelop ER containing these aggregates, indicating induction of ER-phagy. Previous in vitro studies showed that phagophores originate from ER membranes, but the structural relationship between phagophores and the ER membrane in vivo remains unknown. In this study, we used serial block-face scanning electron microscopy to investigate the structural relationship between phagophores, ER membranes, and protein aggregates within dilated ER of AVP neurons from FNDI mice subjected to intermittent water deprivation for 4 weeks. Three-dimensional analysis revealed that phagophores enveloped aggregates located within the dilated ER. Serial imaging further demonstrated a physical connection between these phagophores and intact ER membranes. This study provides the first in vivo evidence of the structural continuity between phagophores and the ER membrane in AVP neurons in a mouse model of FNDI.

The online version contains supplementary material available at 10.1007/s00441-025-04013-w.

Figures