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). Usingin vivogenetic engineering to study disturbed GLE1 functions under physiological conditions we demonstrate that inactivation ofGle1impedes 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-associatedGLE1_FinMajorvariant (Gle1^PFQ/PFQ) survive prenatal period but die suddenly at mid-adulthood.Gle1^PFQ/PFQmice 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 ofGLE1_FinMajorvariant identified normal poly(A)+ RNA distribution inGle1^PFQ/PFQcells, which however were impaired in RNA and protein synthesis and simultaneously showed typical signs of cellular senescence.Gle1^PFQ/PFQalso 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 pathogenicGLE1_FinMajorvariant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects.