GLE1 dysfunction compromises cellular homeostasis, spatial organization, and peripheral axon branching

The GLE1 protein is an enigmatic factor of RNA processing, associated with multiple developmental disorders including lethal congenital contracture syndrome 1 (LCCS1). Using in vivo genetic engineering to study disturbed GLE1 functions under physiological conditions we demonstrate that inactivation of Gle1 impedes cellular function and organization and causes pre-gastrulation lethality due to defects in adhesion and lineage specification. In contrast, the knock-in mice genocopying LCCS1-associated GLE1 _FinMajor variant ( Gle1 ^PFQ/PFQ ) survive prenatal period but die suddenly at mid-adulthood. Gle1 ^PFQ/PFQ mice present irregular count and distribution of spinal motor neurons and impaired development of neural crest-derived tissues as demonstrated by defects in their sympathetic innervation of heart ventricles, paravertebral sympathetic ganglia volume, and adrenal chromaffin cell counts. Unlike previously reported for yeast and HeLa cells, analysis of molecular consequences of GLE1 _FinMajor variant identified normal poly(A)+ RNA distribution in Gle1 ^PFQ/PFQ cells, which however were impaired in RNA and protein synthesis and simultaneously showed typical signs of cellular senescence. Gle1 ^PFQ/PFQ also induced disturbed stress responses with significant changes in G3BP1-positive stress granule count. Our results show necessity of GLE1 functions for life and indicate that LCCS1 etiology is resultant of pathogenic GLE1 _FinMajor variant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects.