Plexin-B2 controls the timing of differentiation and the motility of cerebellar granule neurons

Battum, Eljo van; Heitz-Marchaland, Céline; Zagar, Yvrick; Fouquet, Stéphane; Kuner, Rohini; Chédotal, Alain

doi:10.7554/elife.60554

Cited by 9 publications

(8 citation statements)

References 98 publications

(181 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The top enriched gene-pairs included Tnfrsf1b_Grn, Tnfrsf1a_Grn, Spp1_CD44, Plxnb2_Ptn, Gpr37l1_Psap, and Gpr37_Psap (Figs 6 D, E, S4F, G). For example, Plxnb2 is a transmembrane receptor that participates in axon guidance and cell migration in response to semaphorins [ 94 ]. Plxnb2 is induced in injury-activated microglia and macrophages early after SCI and facilitates the formation of concentric rings of microglia and astrocytes around the necrotic core of the lesion in a mouse model of SCI [ 95 ].…”

Section: Resultsmentioning

confidence: 99%

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Gong

Han

et al. 2022

Neurosci. Bull.

View full text Add to dashboard Cite

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors – the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood–brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.

show abstract

Section: Resultsmentioning

confidence: 99%

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Gong

Han

et al. 2022

Neurosci. Bull.

View full text Add to dashboard Cite

show abstract

“…In mice, it is expressed from embryo to adult ( Perälä et al , 2005 ) and plays an essential role in both central and peripheral neural system development, involving neuronal migration, synaptogenesis, and axonal guidance regeneration ( Saha et al , 2012 ; Van Battum et al , 2021 ), or as a receptor of angiogenin ( Yu et al , 2017 ). Most Plxnb2 −/− mouse embryos, especially in the C57BL/6 strain, show cephalic neural tube closure defects, leading to perinatal lethality or abnormal nervous system development ( Deng et al , 2007 ; Van Battum et al , 2021 ). In Family 3, the euploid miscarriage contained a compound heterozygous mutation in PLXNB2 (p.D1573E and p.R463Q).…”

Section: Resultsmentioning

confidence: 99%

“…Dysregulation of EVT cell migration and invasion is at least partially involved in RM pathogenesis ( Wang et al , 2021 ). It has been shown that PLXNB2 plays an essential role in regulating cellular migration ( Saha et al , 2012 ; Van Battum et al , 2021 ) and tumor invasion ( Gurrapu et al , 2018 ). Our results showed that PLXNB2 knockdown impaired HTR-8/SVneo cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing in unexplained recurrent miscarriage families identified novel pathogenic genetic causes of euploid miscarriage

et al. 2023

View full text Add to dashboard Cite

STUDY QUESTION Can whole exome sequencing (WES) followed by trio bioinformatics analysis identify novel pathogenic genetic causes of first trimester euploid miscarriage? SUMMARY ANSWER We identified genetic variants in six candidate genes that indicated plausible underlying causes of first-trimester euploid miscarriage. WHAT IS KNOWN ALREADY Previous studies have identified several monogenic causes of Mendelian inheritance in euploid miscarriages. However, most of these studies are without trio analyses and lack cellular and animal models to validate the functional effect of putative pathogenic variants. STUDY DESIGN, SIZE, DURATION Eight unexplained recurrent miscarriage (URM) couples and corresponding euploid miscarriages were included in our study for whole genome sequencing (WGS) and WES followed by trio bioinformatics analysis. Knock-in mice with Rry2 and Plxnb2 variants and immortalized human trophoblasts were utilized for functional study. Additional 113 unexplained miscarriages were included to identify the mutation prevalence of specific genes by multiplex PCR. PARTICIPANTS/MATERIALS, SETTING, METHODS Whole blood from URM couples and their <13 weeks gestation miscarriage products were both collected for WES, and all variants in selected genes were verified by Sanger sequencing. Different stage C57BL/6J wild-type mouse embryos were collected for immunofluorescence. Ryr2N1552S/+, Ryr2R137W/+, Plxnb2D1577E/+, and Plxnb2R465Q/+ point mutation mice were generated and backcrossed. Matrigel-coated transwell invasion assays and wound-healing assays were performed using HTR-8/SVneo cells transfected with PLXNB2 small-interfering RNA and negative control. Multiplex PCR was performed focusing on RYR2 and PLXNB2. MAIN RESULTS AND THE ROLE OF CHANCE Six novel candidate genes, including ATP2A2, NAP1L1, RYR2, NRK, PLXNB2, and SSPO, were identified. Immunofluorescence staining showed that ATP2A2, NAP1L1, RyR2, and PLXNB2 were widely expressed from the zygote to the blastocyst stage in mouse embryos. Although compound heterozygous mice with Rry2 and Plxnb2 variants did not show embryonic lethality, the number of pups per litter was significantly reduced when backcrossing Ryr2N1552S/+ ♂ with Ryr2R137W/+ ♀ or Plxnb2D1577E/+ ♂ with Plxnb2R465Q/+ ♀ (P < 0.05), which were in accordance with the sequencing results of Family 2 and Family 3, and the proportion of Ryr2N1552S/+ offspring was significantly lower when Ryr2N1552S/+ female mice were backcrossed with Ryr2R137W/+ male mice (P < 0.05). Moreover, siRNA-mediated PLXNB2 knockdown inhibited the migratory and invasive abilities of immortalized human trophoblasts. Besides, additional 10 variants of RYR2 and PLXNB2 were detected in 113 unexplained euploid miscarriages by multiplex PCR. LIMITATIONS, REASONS FOR CAUTION The relatively small number of samples is a limitation of our study which may result in the identification of variants in unique candidate genes with no definitive although plausible causal effect. Larger cohorts are needed to replicate these findings and additional functional research is needed to confirm the pathogenic effects of these variants. Moreover, the sequencing coverage restricted the detection of low-level parental mosaic variants. WIDER IMPLICATIONS OF THE FINDINGS For first-trimester euploid miscarriage, variants in unique genes may be underlying genetic etiologies and WES on trio could be an ideal model to identify potential genetic causes, which could facilitate individualized precise diagnostic and therapeutic regimens in the future. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from the National Key Research and Development Program of China (2021YFC2700604), National Natural Science Foundation of China (31900492, 82101784, 82171648), Basic Science Center Program of the National Natural Science Foundation of China (31988101), Key Research and Development Program of Shandong Province (2021LCZX02), Natural Science Foundation of Shandong Province (ZR2020QH051), Natural Science Foundation of Jiangsu Province (BK20200223), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201812154) and Young Scholars Program of Shandong University. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

show abstract

“…A reversion of the direction of migration has been described in a wild‐type context for pontine neurons (Shinohara et al., 2013) and cortical interneurons (Tanaka et al., 2009) that can split and retract their leading process. During their tangential migration, cerebellar granule cells also change their polarity, and can migrate bidirectionally and oscillate between their two processes (Renaud & Chédotal, 2014; Van Battum et al., 2021). Our results show that IO neurons axonal extension and migration can also progress in opposite direction when Robo3 is absent.…”

Section: Discussionmentioning

confidence: 99%

Uncoupling axon guidance and neuronal migration in Robo3‐deficient inferior olivary neurons

Moreno-Bravo

Rappeneau

Roig‐Puiggros

et al. 2022

J of Comparative Neurology

Self Cite

View full text Add to dashboard Cite

Inferior olivary (IO) neurons are born in the dorsal hindbrain and migrate tangentially toward the ventral midline. During their dorsoventral migration, IO neurons extend long leading processes that cross the midline, transform into axons, and project into the contralateral cerebellum. In absence of the axon guidance receptor Robo3, IO axons fail to cross the midline and project to the ipsilateral cerebellum. Remarkably, the IO cell bodies still reach the midline where they form a nucleus of abnormal cytoarchitecture. The mechanisms underlying the migration of Robo3-deficient IO neurons are unknown. Here, we used three-dimensional imaging and transgenic mice to label subsets of IO neurons and study their migratory behavior in Robo3 knockout. We show that IO migration is delayed in absence of Robo3. Strikingly, Robo3-deficient IO neurons progress toward the midline in a direction opposite to their axons. This occurs through a change of polarity and the generation of a second leading process at the rear of the cell. These results suggest that Robo3 receptor controls the establishment of neuronal polarity and the coupling of axonogenesis and cell body migration in IO neurons.

show abstract

Plexin-B2 controls the timing of differentiation and the motility of cerebellar granule neurons

Cited by 9 publications

References 98 publications

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury

Whole exome sequencing in unexplained recurrent miscarriage families identified novel pathogenic genetic causes of euploid miscarriage

Uncoupling axon guidance and neuronal migration in Robo3‐deficient inferior olivary neurons

Contact Info

Product

Resources

About