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

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

Alternative Oxidase Expression in the Mouse Enables Bypassing Cytochrome c Oxidase Blockade and Limits Mitochondrial ROS Overproduction

Peer reviewe

Treatment-induced prevention of learning deficits in newborn mice with brain lesions

International audienc

Olfactory classical conditioning in neonatal mouse pups using thermal stimuli

Mouse models are increasingly used to investigate genetic contributions to developmental disorders in children, especially newborns. In particular, early cognitive assessment in newborn mice is critical to evaluate pediatric drug efficacy and toxicity. Unfortunately, methods for behavioral tests in newborn mice are scarce. Therefore, developing such tests for newborn mice is a priority challenge for neurogenetics and pharmacological research. The aim of the present study was to develop a conditioning method well suited to high-throughput cognitive screening in newborn mice. To this end, we developed an odor-preference conditioning test using ambient temperature as an unconditioned stimulus (US) and artificial odors as conditioned stimuli (CS). First, we showed that mouse pups move toward the thermoneutral temperature when offered a choice between a thermoneutral and cold environment, thus showing thermotaxis. Second, we conducted a classical conditioning paradigm in pups aged six to ten days. In terms of central nervous system development, this period corresponds to extreme prematurity to early post-term period in humans. During acquisition, the pups were alternatively exposed to odor CS paired with either cold or warm temperatures. Immediately after acquisition, the pups underwent a two-odor choice test, which showed preference for the odor previously paired with the warm temperature, thus showing conditioning. The proposed paradigm is easy to conduct, and requires modest experimenter interference. The method is well suited for high-throughput screening of early associative disorders in newborn mice.status: publishe