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

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.

Recent insights into the biology of neuroblastoma

“…85 Characterization of heterozygous KI Alk F1178L mice indicated that these mice did not phenocopy the severe neurological disorders, including major feeding and breathing difficulties, observed in the syndromic patients with de novo germline F1245V and F1174V activating ALK mutations. 86 However, we noticed a high lethality of homozygotes between 24 and 48 hr after birth. Evaluation of basic physiological functions 12 hr after birth uncovered a dramatic reduced milk intake for KI Alk F1178L homozygotes, 86 which appears closely related to the feeding difficulties that characterized the patients with encephalopathy.…”

“…Interestingly, Alk activation in sympathetic nervous system ganglia induced opposite effects compared to the ones reported in Ret −/− mice . Characterization of heterozygous KI Alk F1178L mice indicated that these mice did not phenocopy the severe neurological disorders, including major feeding and breathing difficulties, observed in the syndromic patients with de novo germline F1245V and F1174V activating ALK mutations . However, we noticed a high lethality of homozygotes between 24 and 48 hr after birth.…”

“…However, we noticed a high lethality of homozygotes between 24 and 48 hr after birth. Evaluation of basic physiological functions 12 hr after birth uncovered a dramatic reduced milk intake for KI Alk F1178L homozygotes, which appears closely related to the feeding difficulties that characterized the patients with encephalopathy. In contrast to the Alk F1178L mutation, the Alk R1279Q mutation did not induce neonatal lethality in mice when homozygous.…”

A Focus on Regulatory Networks Linking MicroRNAs, Transcription Factors and Target Genes in Neuroblastoma

“…The Anaplastic lymphoma kinase (ALK) gene, originally identified as part of the chimeric nucleophosmin-ALK (NPM-ALK) protein in a chromosomal rearrangement associated with anaplastic large cell lymphoma [ 228 ], maps to chromosome 2p23 and encodes a tyrosine kinase receptor normally expressed at high levels in developing central and peripheral nervous systems districts, such as thalamic nuclei, spinal cord motoneurons and sympathetic, enteric ganglia and motor nuclei of the brainstem [ 229 , 230 , 231 , 232 ]. Its expression has been detected in sympathetic neuroblasts at E12.5 and E13.5 [ 44 ] and it seems to act by inducing neurogenesis in sympathetic ganglia [ 233 , 234 ].…”

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“…Unlike many of the IRK subfamily members, the normal physiological function of ALK is yet to be fully elucidated. There is evidence that ALK plays a role in growth and fetal development of both the central nervous system (CNS) and peripheral nervous system (PNS) [119,120,[122][123][124][125][126][127][128][129]. Furthermore, evidence indicates that constitutively active mutated ALK proteins induce neuronal growth and differentiation [130,131].…”