<i>Drosophila</i>Homolog of Human KIF22 at the Autism-Linked 16p11.2 Loci Influences Synaptic Connectivity at Larval Neuromuscular Junctions

Park, Sang Mee; Littleton, J. Troy; Park, Hae Ryoun; Lee, Ji Hye

doi:10.5607/en.2016.25.1.33

Cited by 24 publications

(30 citation statements)

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“…Choline acetyltransferase, Acetylcholinesterase and Rab4 in Drosophila sensory neurons [ 51 , 52 , 64 – 66 ]. However, they do not directly affect synaptic bouton formation in the NMJs [ 67 ], compelling us to study the direct impact and correlation of the synapse homeostasis in the CNS neuropil.…”

Section: Discussionmentioning

confidence: 99%

A method for estimating relative changes in the synaptic density in Drosophila central nervous system

2018

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BackgroundSynapse density is an essential indicator of development and functioning of the central nervous system. It is estimated indirectly through the accumulation of pre and postsynaptic proteins in tissue sections. 3D reconstruction of the electron microscopic images in serial sections is one of the most definitive means of estimating the formation of active synapses in the brain. It is tedious and highly skill-dependent. Confocal imaging of whole mounts or thick sections of the brain provides a natural alternative for rapid gross estimation of the synapse density in large areas. The optical resolution and other deep-tissue imaging aberrations limit the quantitative scope of this technique.ResultsHere we demonstrate a simple sample preparation method that could enhance the clarity of the confocal images of the neuropil regions of the ventral nerve cord of Drosophila larvae, providing a clear view of synapse distributions. We estimated the gross volume occupied by the synaptic junctions using 3D object counter plug-in of Fiji/ImageJ®. It gave us a proportional estimate of the number of synaptic junctions in the neuropil region. The method is corroborated by correlated super-resolution imaging analysis and through genetic perturbation of synaptogenesis in the larval brain.ConclusionsThe method provides a significant improvement in the relative estimate of region-specific synapse density in the central nervous system. Also, it reduced artifacts in the super-resolution images obtained using the stimulated emission depletion microscopy technique.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0430-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A method for estimating relative changes in the synaptic density in Drosophila central nervous system

2018

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“…KCTD13 encodes a ubiquitin ligase adaptor ( 114 ) that is reported to have reciprocal effects on zebrafish head size with gain- and loss-of-function ( 35 ). KIF22 is a kinesin-like protein that links chromosomes to the mitotic spindle ( 115 , 116 ), and is necessary for proper embryonic chromosome segregation ( 118 ) and synaptic development ( 34 ). SEZ6L2 is a seizure-related protein that modulates neurite outgrowth ( 117 ).…”

Section: Discussionmentioning

confidence: 99%

“…After complete loss-of-function (LOF) in single genes using antisense techniques, we previously found that 22 of 25 homologs were active during early zebrafish development, but only two ( aldoaa and kif22 ) showed haploinsufficient effects on early brain morphology ( 33 ). A small 16p11.2 screen in Drosophila found that a homolog for KIF22 mediated axonal branching patterns ( 34 ). A single study has reported that suppressing and overexpressing kctd13 has reciprocal effects on head size in zebrafish, and the suggestion was made that this reflected the opposing effects of 16p11.2 CNV deletion and duplication on people ( 35 ).…”

Section: Introductionmentioning

confidence: 99%

The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes

McCammon

Blaker-Lee

Chen

et al. 2017

Human Molecular Genetics

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Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity, macrocephaly, and obesity. Available data suggest that most symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brain morphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a genetic interaction not previously described. Using genetic mutants, we demonstrated that doc2a+/− fam57ba+/− double heterozygotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2a−/− or fam57ba−/− mutants. Additionally, doc2a+/− fam57ba+/− double heterozygotes demonstrate the increased body length and head size. Single doc2a+/− and fam57ba+/− heterozygotes do not show a body size increase; however, fam57ba−/− homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction between doc2a and fam57ba. The doc2a+/− fam57ba+/− interaction has not been reported before, nor has any 16p11.2 gene previously been linked to increased body size. These findings demonstrate that one pair of 16p11.2 homologs can regulate both brain and body phenotypes that are reflective of those in people with 16p11.2 deletion. Together, these findings suggest that dysregulation of ceramide pathways and calcium sensitive exocytosis underlies seizures and large body size associated with 16p11.2 homologs in zebrafish. The data inform consideration of mechanisms underlying human 16p11.2 deletion symptoms.

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“…Second , several recent studies using animal and cellular models have demonstrated the critical involvement of several genes within CNVs towards neurological, cellular and developmental functions (36,37,46,47,51,52) ( Figure 2B ). For example, Blaker-Lee et al .…”

Section: A Case For a Multi-genic Model Of Cnv Pathogenicitymentioning

confidence: 96%

An interaction-based model for neuropsychiatric features of copy-number variants

Jensen

Girirajan

2018

Preprint

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18Variably expressive copy-number variants (CNVs) are characterized by extensive phenotypic 19 heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for 20 these phenotypes within each CNV have not been successful. Here, we posit using multiple lines 21 of evidence, including pathogenicity metrics, functional assays of model organisms, and gene 22 expression data, that multiple genes within each CNV region are likely responsible for the 23 observed phenotypes. We propose that candidate genes within each region likely interact with 24 each other through shared pathways to modulate the individual gene phenotypes, emphasizing 25 the genetic complexity of CNV-associated neuropsychiatric features. 26 27 28A case for a multi-genic model of CNV pathogenicity 29 Since the advent of large-scale sequencing studies, the number of genes associated with 30 neurodevelopmental disorders such as autism, intellectual disability, and schizophrenia has 31 increased dramatically. For example, nearly 200 genes have been identified with recurrent de 32 novo mutations in both individuals with autism and intellectual disability (1-8). In fact, complex 33 human disease phenotypes can be influenced by variation in both a small number of core genes 34 with large effect size and a large number of modifier genes with small effect size, accounting for 35 the large number of candidate neurodevelopmental genes (9,10). The application of a multi-genic 36 model for disease pathogenicity has not been fully expanded to cover copy-number variants 37 (CNVs), or large duplications and deletions in the genome. The prevailing notion of single 38 causative genes for CNV disorders is due to the paradigm of gene discoveries for CNVs 39 associated with genetic syndromes in individuals with specific constellations of clinical features, 40 such as Smith-Magenis syndrome (SMS). Although some variability in phenotypic expression 41 has been documented, these disorders usually occur de novo and are characterized by high 42 penetrance for the observed phenotypes (11,12) (Figure 1). In these cases, individuals 43 manifesting the characteristic features of the syndrome but with either atypical breakpoints or 44 mutations in individual genes within the CNV region were used to identify causative genes for 45 the major phenotypes (13-15). These causative genes, such as RAI1 for SMS, were then 46 confirmed by recapitulating conserved phenotypes of the deletion using functional evaluations in 47 animal models (16,17). 48 In contrast, another category of CNVs has been identified in individuals with 49 neurodevelopmental disorders, including duplications and deletions at proximal 16p11.2, 3q29, 50 distal 16p11.2, and 1q21.1 (18-21). Although these CNVs are enriched in affected individuals 51 compared to population controls, they are primarily characterized by variable expressivity of 52 clinical features (12,22-26) (Figure 1B). For example, the 16p11.2 deletion has been implicated 53 in 1% of individuals with idiopathic autism (...

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DrosophilaHomolog of Human KIF22 at the Autism-Linked 16p11.2 Loci Influences Synaptic Connectivity at Larval Neuromuscular Junctions

Cited by 24 publications

References 41 publications

A method for estimating relative changes in the synaptic density in Drosophila central nervous system

A method for estimating relative changes in the synaptic density in Drosophila central nervous system

The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes

An interaction-based model for neuropsychiatric features of copy-number variants

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