Sipa1l3/SPAR3 is targeted to postsynaptic specializations and interacts with the Fezzin ProSAPiP1/Lzts3

Dolnik, Anna; Kanwal, Noreen; Mackert, Sarah; Halbedl, Sonja; Proepper, Christian; Bockmann, Juergen; Schoen, Michael; Boeckers, Tobias M.; Kühl, Susanne J.; Schmeißer, Michael J.

doi:10.1111/jnc.13353

Cited by 17 publications

(17 citation statements)

References 27 publications

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“…In a previous study, we confirmed the genomic conservation of the sipa1l3 gene across species (Dolnik et al, 2016). Here, we showed a similar expression and function of Sipa1l3 in Xenopus compared with mouse and zebrafish (Greenlees et al, 2015;Lachke et al, 2012;Rothe et al, 2016).…”

Section: Sipa1l3 Is Required For Ocular Developmentsupporting

confidence: 66%

“…As Epha4 is located at the cell membrane and Sipa1l3 is located in the cytoplasm close to the cell membrane (Dolnik et al, 2016), we hypothesized Epha4 to be functionally upstream of Sipa1l3. We performed rescue experiments by injecting the Epha4 MO together with rat sipa1l3 RNA and observed a significant reduction in the number of embryos exhibiting eye abnormalities including the microphthalmia phenotype ( Fig.…”

Section: Epha4 Is Upstream Of Sipa1l3 During Xenopus Eye Developmentmentioning

confidence: 99%

“…The open reading frame of rat Sipa1l3 (Dolnik et al, 2016) or chicken Epha4 was cloned into pCS2 + vector using SalI or EcoRI (NEB). The point mutation at amino acid (aa) position 1491 (C>T; Sipa1l3_R1491*) was integrated, leading to a stop codon similar to that of human patients.…”

Section: Cloningmentioning

confidence: 99%

“…All Sipa family members share common domains, namely an N-terminal RapGAP domain (Rap-GTPase activating domain), a PDZ domain and a Cterminal coiled-coil domain that was found to harbor a leucine zipper (Wendholt et al, 2006). So far, Sipa1l1-3 have been analyzed mainly with respect to their synaptic function in the central nervous system (Dolnik et al, 2016;Pak et al, 2001;Spilker et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

et al. 2016

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The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax. We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/β-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts.

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Section: Sipa1l3 Is Required For Ocular Developmentsupporting

confidence: 66%

Section: Epha4 Is Upstream Of Sipa1l3 During Xenopus Eye Developmentmentioning

confidence: 99%

Section: Cloningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

et al. 2016

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“…Here, we report our efforts to identify genetic modifiers in CMT1A on a genome‐wide scale using a large cohort of 971 CMT1A patients. We identified 4 strongly associated intronic variants in signal‐induced proliferation‐associated 1 like 2 ( SIPA1L2 ), also known as spine‐associated RapGAP2 ( SPAR2 ), a member of the Rap GTPase‐activating proteins (RapGAPs) enriched at synaptic sites . Our functional studies imply a role in peripheral nerve myelination and regulating PMP22 expression.…”

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confidence: 84%

Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Tao

Beecham

Rebelo

et al. 2019

Annals of Neurology

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Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a View this article online at wileyonlinelibrary.com.

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Comparative expression study of sipa family members during early Xenopus laevis development

et al. 2016

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The signal-induced proliferation-associated (SIPA) protein family belongs to the RapGAP protein superfamily. Previous studies mainly focused on the expression and function of SIPA genes in vertebrate neuronal tissue. Only limited data about the embryonic expression pattern of the genes are currently available. Our study provides the first expression analysis of sipa1, sipa1l1, sipa1l2, and sipa1l3 during early development of the vertebrate organism Xenopus laevis. In silico, analysis revealed that all genes are highly conserved across species. Semi-quantitative RT-PCR experiments demonstrated that the RNA of all genes was maternally supplied. By whole mount in situ hybridization approaches, we showed that sipa1 is mainly expressed in various sensory organs, the respiratory and blood system, heart, neural tube, and eye. In contrast, sipa1l1 showed a broad expression during development in particular within the brain, somites, eye, and heart. Sipa1l2 was detected in the branchial arches, glomerulus, and the developing eye. In contrast, sipa1l3 revealed a tissue specific expression within the olfactory and otic vesicles, the cranial placodes and ganglia, neural tube, pronephros, retina, and lens. In summary, all sipa gene family members are expressed throughout the whole developing Xenopus organism and might play an important role during vertebrate early embryogenesis.

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Sipa1l3/SPAR3 is targeted to postsynaptic specializations and interacts with the Fezzin ProSAPiP1/Lzts3

Cited by 17 publications

References 27 publications

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Comparative expression study of sipa family members during early Xenopus laevis development

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