DSCAM regulates delamination of neurons in the developing midbrain

Arimura, Nariko; Okada, Mako; Taya, Shinichiro; Dewa, Ken Ichi; Tsuzuki, Akiko; Uetake, Hirotomo; Miyashita, Satoshi; Hashizume, Koichi; Shimaoka, Kazumi; Egusa, Saki F.; Nishioka, Tomoki; Yanagawa, Yuchio; Yamakawa, Kazuhiro; Inoue, Yukiko; Inoue, Tohru; Kaibuchi, Kozo; Hoshino, Mikio

doi:10.1126/sciadv.aba1693

Cited by 20 publications

(23 citation statements)

References 43 publications

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Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 89%

“…Given its role in cell adhesion and repulsion, DSCAM has been proposed to play an important role in the organization of the developing brain [28,[32][33][34][35][36][37][38]. Dscam del17 mutant mice exhibit a prominent and aberrant clumping of neurons in the developing midbrain [28] and retina [17,27,31], thus supporting the hypothesis that DSCAM controls cell spacing. Dscam knockdown studies also impair the radial migration of neurons to upper layers by trapping them in the deep layers and intermediate zone of the developing postnatal cortex [38].…”

Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 89%

“…Cell death markers such as TUNEL and cleaved caspase 3 are decreased in Dscam mutant mice and presumably in DSCAM-expressing cells [27,28], contributing to an aberrant cell proliferation and hypertrophy of several regions in the developing brain of Dscam −/− , Dscam 2J , and Dscam del17 mutant mice [27][28][29][30]. Moreover, as shown by the increased number of cells in the inner retina of Dscam mutant mice, but more modest changes in other layers, this proliferation seems to be cell-specific [17,27,31], thus explaining discrepancies between and within several brain regions upon Dscam mutation.…”

Section: Developmental Programmed Cell Death Pathwaymentioning

confidence: 99%

“…Dscam knockdown studies also impair the radial migration of neurons to upper layers by trapping them in the deep layers and intermediate zone of the developing postnatal cortex [38]. Similarly, knockdown studies also prevent the detachment of nascent cells from ventricles in the developing embryonic midbrain [28]. Molecularly, the cytoplasmic domain of DSCAM appears to interact with RapGEF2 or through a protein complex including RapGEF2, MAGI1, and β-catenin, that suppresses the spontaneous activity of Rap1 and attenuates intercellular adhesions with cadherin molecules, thus supporting the hypothesis that DSCAM plays a role in developing laminar and cellular organization.…”

Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 99%

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Role of DSCAM in the Development of Neural Control of Movement and Locomotion

Lemieux

Thiry

Laflamme

et al. 2021

IJMS

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Locomotion results in an alternance of flexor and extensor muscles between left and right limbs generated by motoneurons that are controlled by the spinal interneuronal circuit. This spinal locomotor circuit is modulated by sensory afferents, which relay proprioceptive and cutaneous inputs that inform the spatial position of limbs in space and potential contacts with our environment respectively, but also by supraspinal descending commands of the brain that allow us to navigate in complex environments, avoid obstacles, chase prey, or flee predators. Although signaling pathways are important in the establishment and maintenance of motor circuits, the role of DSCAM, a cell adherence molecule associated with Down syndrome, has only recently been investigated in the context of motor control and locomotion in the rodent. DSCAM is known to be involved in lamination and delamination, synaptic targeting, axonal guidance, dendritic and cell tiling, axonal fasciculation and branching, programmed cell death, and synaptogenesis, all of which can impact the establishment of motor circuits during development, but also their maintenance through adulthood. We discuss herein how DSCAM is important for proper motor coordination, especially for breathing and locomotion.

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Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 89%

Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 89%

Section: Developmental Programmed Cell Death Pathwaymentioning

confidence: 99%

Section: Laminar Cellular and Dendritic Organizationmentioning

confidence: 99%

See 2 more Smart Citations

Role of DSCAM in the Development of Neural Control of Movement and Locomotion

Lemieux

Thiry

Laflamme

et al. 2021

IJMS

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“…Histological studies: Methods for hippocampal primary neuron culture, immunohistochemistry, and Western blot analyses were described in our papers [25][26][27]. The antibodies used in this study are listed in Additional file 2: Table 1.…”

Section: Methodsmentioning

confidence: 99%

Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility

Hayase

Amano

Hashizume

et al. 2020

acta neuropathol commun

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The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1A2105T protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1A2105T) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans.

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Molecular basis of retinal remodeling in a zebrafish model of retinitis pigmentosa

Santhanam,

Shihabeddin,

Wei

et al. 2023

Cell. Mol. Life Sci.

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A hallmark of inherited retinal degenerative diseases such as retinitis pigmentosa (RP) is progressive structural and functional remodeling of the remaining retinal cells as photoreceptors degenerate. Extensive remodeling of the retina stands as a barrier for the successful implementation of strategies to restore vision. To understand the molecular basis of remodeling, we performed analyses of single-cell transcriptome data from adult zebrafish retina of wild type AB strain (WT) and a P23H mutant rhodopsin transgenic model of RP with continuous degeneration and regeneration. Retinas from both female and male fish were pooled to generate each library, combining data from both sexes. We provide a benchmark atlas of retinal cell type transcriptomes in zebrafish and insight into how each retinal cell type is affected in the P23H model. Oxidative stress is found throughout the retina, with increases in reliance on oxidative metabolism and glycolysis in the affected rods as well as cones, bipolar cells, and retinal ganglion cells. There is also transcriptional evidence for widespread synaptic remodeling and enhancement of glutamatergic transmission in the inner retina. Notably, changes in circadian rhythm regulation are detected in cones, bipolar cells, and retinal pigmented epithelium. We also identify the transcriptomic signatures of retinal progenitor cells and newly formed rods essential for the regenerative process. This comprehensive transcriptomic analysis provides a molecular road map to understand how the retina remodels in the context of chronic retinal degeneration with ongoing regeneration.

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DSCAM regulates delamination of neurons in the developing midbrain

Cited by 20 publications

References 43 publications

Role of DSCAM in the Development of Neural Control of Movement and Locomotion

Role of DSCAM in the Development of Neural Control of Movement and Locomotion

Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility

Molecular basis of retinal remodeling in a zebrafish model of retinitis pigmentosa

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