A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle 1 function in spinal neural precursor survival and motor axon arborization

Li-En Jao, Bruce Appel, Susan R. Wente

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

In humans, GLE1 is mutated in lethal congenital contracture syndrome 1 (LCCS1) leading to prenatal death of all affected fetuses. Although the molecular roles of Gle1 in nuclear mRNA export and translation have been documented, no animal models for this disease have been reported. To elucidate the function of Gle1 in vertebrate development, we used the zebrafish (Danio rerio) model system. gle1 mRNA is maternally deposited and widely expressed. Altering Gle1 using an insertional mutant or antisense morpholinos results in multiple defects, including immobility, small eyes, diminished pharyngeal arches, curved body axis, edema, underdeveloped intestine and cell death in the central nervous system. These phenotypes parallel those observed in LCCS1 human fetuses. Gle1 depletion also results in reduction of motoneurons and aberrant arborization of motor axons. Unexpectedly, the motoneuron deficiency results from apoptosis of neural precursors, not of differentiated motoneurons. Mosaic analyses further indicate that Gle1 activity is required extrinsically in the environment for normal motor axon arborization. Importantly, the zebrafish phenotypes caused by Gle1 deficiency are only rescued by expressing wild-type human GLE1 and not by the disease-linked Fin Major mutant form of GLE1. Together, our studies provide the first functional characterization of Gle1 in vertebrate development and reveal its essential role in actively dividing cells. We propose that defective GLE1 function in human LCCS1 results in both neurogenic and non-neurogenic defects linked to the apoptosis of proliferative organ precursors.

Original languageEnglish (US)
Pages (from-to)1316-1326
Number of pages11
JournalDevelopment
Volume139
Issue number7
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Fingerprint

Zebrafish
Axons
Motor Neurons
Survival
Vertebrates
Fetus
Apoptosis
Branchial Region
Phenotype
Animal Disease Models
Morpholinos
Cell Nucleus Active Transport
Protein Biosynthesis
Intestines
Edema
Cell Death
Central Nervous System
Messenger RNA
Lethal congenital contracture syndrome 1

Keywords

  • mRNA metabolism
  • Neurodegeneration
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle 1 function in spinal neural precursor survival and motor axon arborization. / Jao, Li-En; Appel, Bruce; Wente, Susan R.

In: Development, Vol. 139, No. 7, 01.04.2012, p. 1316-1326.

Research output: Contribution to journalArticle

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