Affordable Access

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

Authors
  • Lopez-Delisle, Lucille
  • Pierre-Eugène, Cécile
  • Bloch-Gallego, Evelyne
  • Birling, Marie-Christine
  • Duband, Jean-Loup
  • Durand, Estelle
  • Bourgeois, Thomas
  • Matrot, Boris
  • Sorg, Tania
  • Huerre, Michel
  • Meziane, Hamid
  • Roux, Michel J
  • Champy, Marie-France
  • Gallego, Jorge
  • Delattre, Olivier
  • Janoueix-Lerosey, Isabelle
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
May 15, 2014
Volume
5
Issue
9
Pages
2703–2713
Identifiers
PMID: 24811761
Source
Medline
License
Unknown

Abstract

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.

Report this publication

Statistics

Seen <100 times