The Receptor Tyrosine Kinase Alk Controls Neurofibromin Functions in Drosophila Growth and Learning

Gouzi, Jean Y.; Moressis, Anastasios; Walker, James A.; Apostolopoulou, Anthi A.; Palmer, Ruth; Bernards, André; Skoulakis, Efthimios M. C.

doi:10.1371/journal.pgen.1002281

Cited by 95 publications

(146 citation statements)

References 66 publications

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“…Results of the second study, suggested a decreased anxiety for Alk mutants and an increased performance in spatial memory. Interestingly, this phenotype is consistent with the one described in Drosophila , since dAlk inhibition was shown to enhance olfactory associative learning in this model organism [15]. It therefore appears that whereas Alk inhibition decreases anxiety in mice, Alk activation induces an opposite effect.…”

Section: Discussionsupporting

confidence: 88%

“…Drosophila embryos lacking dALK die due to abnormalities in the formation of gut musculature [13] and the dALK receptor is also involved in the neuronal circuit assembly of the visual system [14]. More recently, it has been shown that dALK plays critical roles in body size determination and associative olfactory learning [15] and that it permits central nervous system (CNS) growth under nutrient restriction [16]. In contrast to Drosophila , mice deficient in Alk are viable, fertile and display a normal appearance [17,18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Nf1 +/− mice have higher levels of phosphorylated ERK in the brain and basal GABA release (Cui et al, 2008; Repunte-Canonigo et al, 2015), also similar to what we found in Alk −/− mice. In Drosophila , genetic or pharmacological inhibition of Alk rescues the increased ERK activation and associative learning deficits observed in Nf1 mutants (Gouzi et al, 2011), suggesting that ALK and NF1 function in the same intracellular signaling pathway. These results, combined with the human genetic association studies that implicate the NF1 and ALK genes in alcohol dependence (Repunte-Canonigo et al, 2015; Wang et al, 2011), support the possibility that ALK may play an active role in dependence-induced drinking through regulation of the Ras/ERK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

et al. 2016

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk −/−) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk −/− mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk −/− mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk −/− mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk −/− mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA.

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“…By contrast, activation of the KIT receptor by stem cell factor (also known as KIT ligand) has a key role in neurofibroma formation in mice 62 . In Drosophila melanogaster expressing mutant Nf1 , the loss of the receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) rescues the small size of the flies and ERK activation 84 . Other receptors probably function as upstream regulators of neurofibromin in specific cell types.…”

Section: Neurofibromin Regulation and Signallingmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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The Receptor Tyrosine Kinase Alk Controls Neurofibromin Functions in Drosophila Growth and Learning

Cited by 95 publications

References 66 publications

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

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

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

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