Fine mapping of<i>AHI1</i>as a schizophrenia susceptibility gene: from association to evolutionary evidence

Torri, Federica; Akelai, Anna; Lupoli, Sara; Sironi, Manuela; Amann‐Zalcenstein, Daniela; Fumagalli, Matteo; Fiume, Chiara Dal; Ben-Asher, Edna; Kanyas, Kyra; Cagliani, Rachele; Cozzi, Paolo; Trombetti, Gabriele; Lievers, Luisa Strik; Orro, Alessandro; Beckmann, Jacques S.; Lancet, Doron; Kohn, Yoav; Milanesi, Luciano; Ebstein, Richard P.; Lerer, Bernard; Macciardi, Fabìo

doi:10.1096/fj.09-152611

Cited by 39 publications

(41 citation statements)

References 127 publications

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“…Therefore, our study has identified a major role of MAP7 in the developmental regulation of collateral branch formation of DRG sensory axons. Because MAP7 has been associated recently with autism and schizophrenia (Torri et al, 2010;Venkatasubramanian, 2015;Rouillard et al, 2016), one can imagine that it influences branch morphogenesis of other neuronal cell types that are critical to these neurological disorders. Therefore, it would be interesting to further analyze MAP7 function in other parts of the nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, the only known MAP7 function is linked to spermatogenesis and histocompatibility (Komada et al, 2000;Magnan et al, 2009). Despite its expression in the nervous system (FabreJonca et al, 1998;Komada et al, 2000) and the recent finding of MAP7 association with autism and schizophrenia (Torri et al, 2010;Venkatasubramanian, 2015;Rouillard et al, 2016), the function of MAP7 in neurons has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons

et al. 2017

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Collateral branches from axons are key components of functional neural circuits that allow neurons to connect with multiple synaptic targets. Like axon growth and guidance, formation of collateral branches depends on the regulation of microtubules, but how such regulation is coordinated to ensure proper circuit development is not known. Based on microarray analysis, we have identified a role for microtubule-associated protein 7 (MAP7) during collateral branch development of dorsal root ganglion (DRG) sensory neurons. We show that MAP7 is expressed at the onset of collateral branch formation. Perturbation of its expression by overexpression or shRNA knockdown alters axon branching in cultured DRG neurons. Localization and time-lapse imaging analysis reveals that MAP7 is enriched at branch points and colocalizes with stable microtubules, but enters the new branch with a delay, suggesting a role in branch maturation. We have also investigated a spontaneous mutant mouse that expresses a truncated MAP7 and found a gain-of-function phenotype both in vitro and in vivo. Further domain analysis suggests that the amino half of MAP7 is responsible for branch formation, suggesting a mechanism thatisindependentofitsknowninteractionwithkinesin.Moreover,thismouseexhibitsincreasedpainsensitivity,aphenotypethatisconsistent with increased collateral branch formation. Therefore, our study not only uncovers the first neuronal function of MAP7, but also demonstrates the importance of proper microtubule regulation in neural circuit development. Furthermore, our data provide new insights into microtubule regulation during axonal morphogenesis and may shed light on MAP7 function in neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons

et al. 2017

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“…Therefore, it is conceivable that variants affecting cognition are still evolving adaptively in anatomically modern humans [4,38], although no specific evidence for this has been reported to date. While several genes involved in neural development and cognitive performances have been identified as targets of natural selection in modern human populations [14,25,30,53,64], none of their polymorphisms has been reliably shown to influence intelligence, the only exception being a nonsynonymous SNP in BDNF [36]. Still, in this latter case the Met66 allele, which is thought to have been driven to high frequency by selection, has a negative impact on cognitive abilities [12].…”

Section: Introductionmentioning

confidence: 99%

Variants in SNAP25 are targets of natural selection and influence verbal performances in women

Cagliani

Riva

Marino

et al. 2011

Cell. Mol. Life Sci.

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Descriptions of genes that are adaptively evolving in humans and that carry polymorphisms with an effect on cognitive performances have been virtually absent. SNAP25 encodes a presynaptic protein with a role in regulation of neurotransmitter release. We analysed the intra-specific diversity along SNAP25 and identified a region in intron 1 that shows signatures of balancing selection in humans. The estimated TMRCA (time to the most recent common ancestor) of the SNAP25 haplotype phylogeny amounted to 2.08 million years. The balancing selection signature is not secondary to demographic events or to biased gene conversion, and encompasses rs363039. This SNP has previously been associated to cognitive performances with contrasting results in different populations. We analysed this variant in two Italian cohorts in different age ranges and observed a significant genotype effect for rs363039 on verbal performances in females alone. Post hoc analysis revealed that the effect is driven by differences between heterozygotes and both homozygous genotypes. Thus, heterozygote females for rs363039 display higher verbal performances compared to both homozygotes. This finding was replicated in a cohort of Italian subjects suffering from neuromuscular diseases that do not affect cognition. Heterozygote advantage is one of the possible reasons underlying the maintenance of genetic diversity in natural populations. The observation that heterozygotes for rs363039 display higher verbal abilities compared to homozygotes perfectly fits the underlying balancing selection model. Although caution should be used in inferring selective pressures from observed signatures, SNAP25 might represent the first description of an adaptively evolving gene with a role in cognition.

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“…Later studies revealed that nonsense or frame-shift mutations in AHI1 are associated with Joubert syndrome, a rare autosomal recessive disorder characterized by abnormal brain development and mental retardation (2,3). Recently, fine mapping (4,5), association (6), and replication (7,8) studies have identified AHI1 as a susceptibility gene for schizophrenia, a major neuropsychiatric disorder associated with depression. The AHI1 gene locus has also been linked with autism, which overlaps with a schizophrenia haplotype (9) and is also seen in some patients with Joubert syndrome (10).…”

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confidence: 99%

Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype

Yang

Lin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies suggest that the human Abelson helper integration site-1 (AHI1) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre-loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression.neuropathology | neuropsychiatric | neurotrophic | endocytosis | trafficking

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Fine mapping ofAHI1as a schizophrenia susceptibility gene: from association to evolutionary evidence

Cited by 39 publications

References 127 publications

MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons

MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons

Variants in SNAP25 are targets of natural selection and influence verbal performances in women

Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype

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