Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

Taylor, Matthew R. G.; Martin, Elizabeth A.; Sinnen, Brooke L.; Trilokekar, Rajdeep; Ranza, Emmanuelle; Antonarakis, Stylianos E.; Williams, Megan E.

doi:10.1101/2019.12.30.891085

Cited by 4 publications

(10 citation statements)

References 68 publications

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“…In support of additional dimerization sites, Gerke et al (2003) reported evidence that dimerization was not limited to any single domain within Kirrel1 and the related Nephrin. Furthermore, a large number of human mutations affecting Kirrel3 function in the ectodomain, but outside D1, have been identified (summarized in Taylor et al, 2020). To test whether Kirrel ectodomains can form dimers using interfaces we did not identify in our crystal structures, we used analytical ultracentrifugation to quantify dimerization of Kirrel2 and Kirrel3 ectodomains and one D1 interface mutant, Kirrel3 Q128A.…”

Section: Resultsmentioning

confidence: 99%

“…We therefore studied the entire Kirrel2 and Kirrel3 ectodomains using Multiple lines of evidence support the idea that Kirrels and its homologs act as more than "molecular Velcro" in nervous system development. In the hippocampus, Kirrel3 homophilic adhesion is required, but not sufficient for synapse formation, and mutations that occur outside of the D1 binding domains and even in the intracellular domains prevent synapse formation, despite being able to form homodimeric complexes (Taylor et al, 2020). The C. elegans homologs SYG-1 and SYG-2 were shown to be signaling receptors, whose functions depend on the exact geometry of ectodomain dimerization also mediated by D1 (Özkan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Loss of Kirrel2 and Kirrel3 causes disorganization of a subset of glomeruli in the main and accessory olfactory bulbs (Brignall et al, 2018; Nakashima et al, 2019; Prince et al, 2013; Vaddadi et al, 2019), and Kirrel3 knockout mice show behavioral abnormalities similar to those in autistic patients, including defects in social responses, auditory sensory processing and communication, and repetitive behaviors (Hisaoka et al, 2018; Völker et al, 2018), in addition to loss of male-male aggression likely as a result of miswiring in the AOB (Prince et al, 2013). Furthermore, several mutations in human autism and intellectual disability patients were identified (see Taylor et al, 2020 for a list). To our surprise, none of the missense mutations are in the first domain, including mutations recently reported to affect Kirrel3-mediated cell adhesion (Taylor et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several mutations in human autism and intellectual disability patients were identified (see Taylor et al, 2020 for a list). To our surprise, none of the missense mutations are in the first domain, including mutations recently reported to affect Kirrel3-mediated cell adhesion (Taylor et al, 2020). We therefore studied the entire Kirrel2 and Kirrel3 ectodomains using a combination of biophysical methods, but could not produce evidence that there are secondary binding sites outside the D1-D1 interface.…”

Section: Discussionmentioning

confidence: 99%

“…The C. elegans homolog, SYG-1, has been demonstrated to specify targeting of synapses (Shen and Bargmann, 2003). Outside its function in the olfactory system, mammalian Kirrel3 has been shown to be a synaptic adhesion molecule necessary for the formation of a group of synapses in the hippocampus (Martin et al, 2015; Taylor et al, 2020), and is associated with autism spectrum disorders and intellectual disability (Bhalla et al, 2008; De Rubeis et al, 2014; Taylor et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

Wang

Vaddadi

Pak

et al. 2021

Preprint

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Projections from sensory neurons of olfactory systems coalesce into glomeruli in the brain. The Kirrel receptors are believed to homodimerize via their ectodomains and help separate sensory neuron axons into Kirrel2- or Kirrel3-expressing glomeruli. Here we present the crystal structures of homodimeric Kirrel receptors and show that the closely related Kirrel2 and Kirrel3 have evolved specific sets of polar and hydrophobic interactions, respectively, disallowing heterodimerization while preserving homodimerization, likely resulting in proper segregation and coalescence of Kirrel-expressing axons into glomeruli. We show that the dimerization interface at the N-terminal IG domains is necessary and sufficient to create homodimers, and fail to find evidence for a secondary interaction site in Kirrel ectodomains. Furthermore, we show that abolishing dimerization of Kirrel3 in vivo leads to improper formation of glomeruli in the mouse accessory olfactory bulb as observed in Kirrel3-/- animals. Our results provide strong evidence for Kirrel3 homodimerization controlling axonal coalescence.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

Wang

Vaddadi

Pak

et al. 2021

Preprint

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A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia

et al. 2021

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KIRREL3 is a gene important for the central nervous system development—in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis—and colocalizes and cooperates in neurons with CASK gene. Alterations of KIRREL3 have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of KIRREL3 partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo KIRREL3 mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant KIRREL3 variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between KIRREL3 and CASK, we discuss as posterior fossa anomalies may also be part of the phenotype of KIRREL3-related syndrome.

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Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

Wang

Huang

Ang

et al. 2023

Preprint

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Cerebrovascular damage coexists with Alzheimers disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.

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Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

Abstract: word count: 209 21

Cited by 4 publications

References 68 publications

Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

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