IgSF molecule MDGA1 is involved in radial migration and positioning of a subset of cortical upper‐layer neurons

Ishikawa, Takao; Gotoh, Naoya; Murayama, Chiaki; Abe, Takaya; Iwashita, Misato; Matsuzaki, Fumio; Suzuki, Toshiharu; Yamamoto, Tohru

doi:10.1002/dvdy.22496

Cited by 26 publications

(33 citation statements)

References 59 publications

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“…Our results replicate previous reports of expression of Cntn6 in anterior thalamic nuclei [74, 75]. Mdga1 is expressed in a layer- and area-specific manner in the cortex [76] and mutation of the gene leads to a delay in cortical neuronal migration [77]. More recently, Mdga1 has also been found to interact with neuroligin-2 to negatively regulate inhibitory synapse formation [78, 79].…”

Section: Resultssupporting

confidence: 91%

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

et al. 2017

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The thalamus or “inner chamber” of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity.

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Section: Resultssupporting

confidence: 91%

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

et al. 2017

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“…MDGAs are highly expressed in the developing brain (12,15,16). Knockout of MDGA1 causes a discrete phenotype in neuronal migration and impairs rostral growth of commissural axons, suggesting an important role during the initial development of the brain (17,18). Interestingly, SNP-based, large-scale human genetic analyses suggested that MDGA1 and MDGA2 may be susceptibility genes for schizophrenia, bipolar disorder, and autism spectrum disorder (19)(20)(21).…”

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confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

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

118

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The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

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“…It is noteworthy that while Mdga2 over-expression largely rescued the deficit, there was not a complete rescue. Interestingly, Mdga1 , Mdga2 closest homologue, is required for neuronal migration [44], [45]. Thus, while Mdga2 plays a major role in Laf4-regulated migration, it may not be the only effector gene.…”

Section: Discussionmentioning

confidence: 99%

Laf4/Aff3, a Gene Involved in Intellectual Disability, Is Required for Cellular Migration in the Mouse Cerebral Cortex

et al. 2014

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Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets. For example, deletion of human lymphoid nuclear protein related to AF4/AFF member 3 (LAF4/AFF3) is known to cause severe neurodevelopmental defects, and silencing of the gene is also associated with ID at the folate-sensitive fragile site (FSFS) FRA2A; yet the normal function of this gene in the nervous system is unclear. The aim of this study was to further investigate the function of Laf4 in the brain by focusing on its role in the cortex. By manipulating expression levels in organotypic slices, we demonstrate here that Laf4 is required for normal cellular migration in the developing cortex and have subsequently identified Mdga2, an important structural protein in neurodevelopment, as a target of Laf4 transcriptional activity. Furthermore, we show that the migration deficit caused by loss of Laf4 can be partially rescued by Mdga2 over-expression, revealing an important functional relationship between these genes. Our study demonstrates the key transcriptional role of Laf4 during early brain development and reveals a novel function for the gene in the process of cortical cell migration relevant to the haploinsufficiency and silencing observed in human neurodevelopmental disorders.

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IgSF molecule MDGA1 is involved in radial migration and positioning of a subset of cortical upper‐layer neurons

Cited by 26 publications

References 59 publications

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Laf4/Aff3, a Gene Involved in Intellectual Disability, Is Required for Cellular Migration in the Mouse Cerebral Cortex

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