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Radial glia, basal lamina, and granule cell migration in Plexin-B2-deficient mice. A-H, Sagittal cerebellum sections immunostained for GFAP (A-D, G, H ), laminin (C-F ), and Pax6 (G, H ). Normal radial glia palisade in adult (A), P15 (C), or P11 (G) Plexin-B2 / . In contrast, the radial glia palisade is very perturbed in adult (B), P15 (D), and P11 (H ) Plexin-B2 / , although radial glia fibers still extend to the pial surface and form typical end feet (arrowheads in D). C, D, Laminin expression at the GFAP-positive radial glia end feet is similar in P15 Plexin-B2 / (C) and Plexin-B2 / (D) mice. E, F, In adult, Plexin-B2 / (E) and Plexin-B2 / (F ) laminin is highly expressed in the basal lamina covering each cerebellar folia. The staining is similar in heterozygous and homozygous. G, H, At P11, radially migrating Pax6-expressing granule cells can be observed apposed to GFAP-positive radial glia fibers both in Plexin-B2 / and in Plexin-B2 / (arrowheads in G, H ). Scale bars: A, B, 270 m; C, D, 50 m; E, F, 220 m; G, H, 35 m.
Source publication
Cerebellar granule cell progenitors proliferate postnatally in the upper part of the external granule cell layer (EGL) of the cerebellum. Postmitotic granule cells differentiate and migrate, tangentially in the EGL and then radially through the molecular and Purkinje cell layers. The molecular control of the transition between proliferation and dif...
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... of the radial glia palisade between Plexin-B2 / and Plexin-B2 / (data not shown). At P11 and in adults, the palisade of radial glia was perturbed in Plexin-B2 / cerebellum with many fibers having curved and irregular courses. However, GFAP-labeled radial glia fibers still extended to the pial surface and formed characteristic end feet (Fig. 4 A-D,G,H ). In the cerebellum of P11 Plexin-B2 / mice, Pax6-immunopositive granule cells were frequently observed apposed to Bergmann glia fibers, suggesting that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). ...
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... curved and irregular courses. However, GFAP-labeled radial glia fibers still extended to the pial surface and formed characteristic end feet (Fig. 4 A-D,G,H ). In the cerebellum of P11 Plexin-B2 / mice, Pax6-immunopositive granule cells were frequently observed apposed to Bergmann glia fibers, suggesting that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). Last, the expression and distribution of the extracellular matrix protein laminin was identical in Plexin-B2 / and Plexin-B2 / , both at P15 and in adults (Fig. 4C-F ). These results suggest that ...
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... that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). Last, the expression and distribution of the extracellular matrix protein laminin was identical in Plexin-B2 / and Plexin-B2 / , both at P15 and in adults (Fig. 4C-F ). These results suggest that Plexin-B2 deficiency does not cause major granule cells migration ...
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... that Sema4D is only expressed by oligodendrocytes in the postnatal brain (Moreau-Fauvarque et al., 2003) and thus may not be a Plexin-B2 ligand in the EGL. We studied the expression pattern of the five other class 4 semaphorins at P10, the peak of granule cell proliferation. Sema4A was expressed at a low level in the Purkinje layer (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Sema4B was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly ...
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... five other class 4 semaphorins at P10, the peak of granule cell proliferation. Sema4A was expressed at a low level in the Purkinje layer (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Sema4B was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly expressed mostly in the lower part of the EGL and in the IGL (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Last, Sema4G was expressed by Purkinje cells. We next ...
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... was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly expressed mostly in the lower part of the EGL and in the IGL (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Last, Sema4G was expressed by Purkinje cells. We next analyzed cerebellum organization in mice single or double deficient for the class 4 semaphorins Sema4A ( Kumanogoh et al., 2005) and Sema4D ( Kumanogoh et al., 2002), which are all viable and have no obvious brain defect. We ...
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... ( Kumanogoh et al., 2002), which are all viable and have no obvious brain defect. We first stained sections from P30 cerebellum with Nissl or antibodies against CaBP, neuronalspecific nuclear protein, and 6. Neither cerebellar defects nor ectopic granule cells were observed in Sema4A, Sema4D, and Sema4A/Sema4D double knock-outs (supplemental Fig. 4, available at www.jneurosci.org as supplemental material) (data not shown). (A, C, E, G, I-L, Q, R) and Plexin-B2 / (B, D, F, H, M-P, S, T ) mice. A, B, Section of E14 embryos immunostained with Pax6 and -gal antibodies. The development of the EGL (arrowheads) and the distribution of granule cell progenitors coexpressing Pax6 and -gal ...
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... of the radial glia palisade between Plexin-B2 / and Plexin-B2 / (data not shown). At P11 and in adults, the palisade of radial glia was perturbed in Plexin-B2 / cerebellum with many fibers having curved and irregular courses. However, GFAP-labeled radial glia fibers still extended to the pial surface and formed characteristic end feet (Fig. 4 A-D,G,H ). In the cerebellum of P11 Plexin-B2 / mice, Pax6-immunopositive granule cells were frequently observed apposed to Bergmann glia fibers, suggesting that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). ...
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... curved and irregular courses. However, GFAP-labeled radial glia fibers still extended to the pial surface and formed characteristic end feet (Fig. 4 A-D,G,H ). In the cerebellum of P11 Plexin-B2 / mice, Pax6-immunopositive granule cells were frequently observed apposed to Bergmann glia fibers, suggesting that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). Last, the expression and distribution of the extracellular matrix protein laminin was identical in Plexin-B2 / and Plexin-B2 / , both at P15 and in adults (Fig. 4C-F ). These results suggest that ...
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... that radial migration was not altered (Fig. 4G,H ). Accordingly, only a few ectopic cells remain close to the surface or in the molecular layer in the adult mutant cerebellum (Fig. 2). Last, the expression and distribution of the extracellular matrix protein laminin was identical in Plexin-B2 / and Plexin-B2 / , both at P15 and in adults (Fig. 4C-F ). These results suggest that Plexin-B2 deficiency does not cause major granule cells migration ...
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... that Sema4D is only expressed by oligodendrocytes in the postnatal brain (Moreau-Fauvarque et al., 2003) and thus may not be a Plexin-B2 ligand in the EGL. We studied the expression pattern of the five other class 4 semaphorins at P10, the peak of granule cell proliferation. Sema4A was expressed at a low level in the Purkinje layer (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Sema4B was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly ...
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... five other class 4 semaphorins at P10, the peak of granule cell proliferation. Sema4A was expressed at a low level in the Purkinje layer (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Sema4B was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly expressed mostly in the lower part of the EGL and in the IGL (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Last, Sema4G was expressed by Purkinje cells. We next ...
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... was also expressed in the Purkinje cell layer but most likely by Bergman glia cells and not by Purkinje cells (supplemental Fig. 4, available at www. jneurosci.org as supplemental material, compare with Sema4G staining of Purkinje cells). Sema4C and Sema4F were weakly expressed mostly in the lower part of the EGL and in the IGL (supplemental Fig. 4, available at www.jneurosci.org as supplemental material). Last, Sema4G was expressed by Purkinje cells. We next analyzed cerebellum organization in mice single or double deficient for the class 4 semaphorins Sema4A ( Kumanogoh et al., 2005) and Sema4D ( Kumanogoh et al., 2002), which are all viable and have no obvious brain defect. We ...
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... ( Kumanogoh et al., 2002), which are all viable and have no obvious brain defect. We first stained sections from P30 cerebellum with Nissl or antibodies against CaBP, neuronalspecific nuclear protein, and 6. Neither cerebellar defects nor ectopic granule cells were observed in Sema4A, Sema4D, and Sema4A/Sema4D double knock-outs (supplemental Fig. 4, available at www.jneurosci.org as supplemental material) (data not shown). (A, C, E, G, I-L, Q, R) and Plexin-B2 / (B, D, F, H, M-P, S, T ) mice. A, B, Section of E14 embryos immunostained with Pax6 and -gal antibodies. The development of the EGL (arrowheads) and the distribution of granule cell progenitors coexpressing Pax6 and -gal ...
Citations
... Despite the knockout mice having no obvious behavioural or motor defects, their cerebella were smaller and major brain foliation defects were still present. 12 Heterozygous Plxnb2 +/mice had no apparent abnormalities. ...
... Pathogenic variants in PLXNA1 cause an overlapping and similarly varying range of phenotypes to pathogenic variants in PLXNB2. 23 The impact of genetic background on variation in disease phenotype, severity and survival has been noted for one Plxnb2 -/mouse model, 12 which suggests that other cosegregating variants may affect disease range and severity. This may suggest that, in spite of the distinct patterns of plexin expression, 8 other plexins can sometimes partially compensate for loss of PLXNB2 or PLXNA1 to allow developmental processes vital to life to proceed. ...
Background
Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease.
Methods
Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.
Results
Rare biallelic pathogenic variants in plexin B2 ( PLXNB2 ), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts.
Conclusion
We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
... A previous study of Tnmd knockout mice demonstrated that TEMD deficiency causes hampered running performance, and TEMD is essential to tendon endurance running [97]. The mouse Plxnb2 gene was reported to control cerebellar granule cells' development [98], and the human PLXNB2 gene was suggested to be relevant to amyotrophic lateral sclerosis (ALS) pathogenesis [99]. Mutations in the human SBF1 gene were identified to cause motor and sensory neuropathies [100,101]. ...
The complicated interactions between genetic background, environment and lifestyle factors make it difficult to study the genetic basis of complex phenotypes, such as cognition and anxiety levels, in humans. However, environmental and other factors can be tightly controlled in mouse studies. The Collaborative Cross (CC) is a mouse genetic reference population whose common genetic and phenotypic diversity is on par with that of humans. Therefore, we leveraged the power of the CC to assess 52 behavioral measures associated with locomotor activity, anxiety level, learning and memory. This is the first application of the CC in novel object recognition tests, Morris water maze tasks, and fear conditioning tests. We found substantial continuous behavioral variations across the CC strains tested, and mapped six quantitative trait loci (QTLs) which influenced these traits, defining candidate genetic variants underlying these QTLs. Overall, our findings highlight the potential of the CC population in behavioral genetic research, while the identified genomic loci and genes driving the variation of relevant behavioral traits provide a foundation for further studies.
... Semaphorins4C (sema4C) is also an important member of sema4, which has been extensively studied in nerve development. sema4C mutant mice displayed obvious cerebellar defects, leading to neonatal death [18]. Furthermore, studies have demonstrated that sema4C was also implicated in biological events outside the nervous system, such as cell migration [19], tumor development [20], and terminal myogenic differentiation [21]. ...
Endothelial cells (ECs) and neurons share a number of common signaling pathways and molecular mediators to orchestrate directional migration and guide the pattern of the vascular network and nervous system. So far, research concerning the functional coupling between vascular and neuronal pathfinding remains insufficient. Semaphorin4C (sema4C), a member of class 4 semaphorins, is initially described in the nervous system, whose role has been demonstrated in diverse biological developments. The present study focused on the role of sema4C in the vascular and neural development process in zebrafish embryos. It confirmed that sema4C is expressed in both the nervous system and intersegmental vessels (ISVs) in zebrafish embryos by diverse expression analysis. It also showed that the knockdown of sema4C caused a serious pathfinding anomaly both in the ISVs and primary motor neurons (PMNs) of zebrafish embryos. In addition, overexpressing exogenous sema4C mRNA in sema4C morphants remarkably neutralized the defective pattern of the vascular and neural system. Collectively, this report suggests that sema4C acts as a dual guiding factor regulating vascular and neuronal development. These findings elucidate a new molecular mechanism underlying blood vessel and nerve development and might serve as groundwork for future research on functional coupling between both systems.
... Plexin-B2 is an axon guidance receptor widely expressed in the developing brain, in particular at the ventricular surface, supporting its role in regulating neuroprogenitors 11 . Plexin-B2 plays an essential role in neural tube closure and cerebellar granule cell migration during neurodevelopment [12][13][14] . Mouse mutant studies also revealed a role of Plexin-B2 in coordinating the proliferation and migration of neuroblasts in the rostral migratory stream 12,13,15,16 . ...
... Plexin-B2 plays an essential role in neural tube closure and cerebellar granule cell migration during neurodevelopment [12][13][14] . Mouse mutant studies also revealed a role of Plexin-B2 in coordinating the proliferation and migration of neuroblasts in the rostral migratory stream 12,13,15,16 . Plexin-B2 is also expressed in brain tumor cells 17 and epidermal stem cells 18 . ...
... The mechanoregulatory function of Plexin-B2 is more critical for structurally complex tissues such as ventricular zones and neuroepithelium. In cerebral organoids, Plexin-B2 perturbation caused ventricular malformation, reminiscent of the neural tube closure defect seen in Plxnb2 KO mice 12 , and echoing earlier reports that neural tube closure defect can arise from dysregulated mechanical interactions and tissue tension, thereby impacting cellular alignment and NPC function 10 . Our study also has implications for development and cancer. ...
During morphogenesis, molecular mechanisms that orchestrate biomechanical dynamics across cells remain unclear. Here, we show a role of guidance receptor Plexin-B2 in organizing actomyosin network and adhesion complexes during multicellular development of human embryonic stem cells and neuroprogenitor cells. Plexin-B2 manipulations affect actomyosin contractility, leading to changes in cell stiffness and cytoskeletal tension, as well as cell-cell and cell-matrix adhesion. We have delineated the functional domains of Plexin-B2, RAP1/2 effectors, and the signaling association with ERK1/2, calcium activation, and YAP mechanosensor, thus providing a mechanistic link between Plexin-B2-mediated cytoskeletal tension and stem cell physiology. Plexin-B2-deficient stem cells exhibit premature lineage commitment, and a balanced level of Plexin-B2 activity is critical for maintaining cytoarchitectural integrity of the developing neuroepithelium, as modeled in cerebral organoids. Our studies thus establish a significant function of Plexin-B2 in orchestrating cytoskeletal tension and cell-cell/cell-matrix adhesion, therefore solidifying the importance of collective cell mechanics in governing stem cell physiology and tissue morphogenesis. Biomechanical mechanisms orchestrating stem cell dynamics in development remain unclear. Here the authors show that guidance receptor Plexin-B2 organizes actomyosin contractility, cytoskeletal tension and adhesion during multicellular development of human embryonic stem cells and neuroprogenitor cells.
... Moreover, animal models suggest a role of CELSR1 in yielding reduced numbers of cortical neurons and abnormal brain architecture (Boucherie et al., 2018). PLXNB2 knockout mice show aberrant granule cell proliferation and differentiation, leading to reduced cerebellar fissure formation and fusion of cerebellar folia (Friedel et al., 2007). ...
Phelan‐McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2‐q13.33 terminal deletion detected in our sample of 63 PMS patients by array‐CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co‐dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype–phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence‐based genetic work‐ups, clinical assessments, and therapeutic interventions.
... However, potential functions of class 4 semaphorins and Btype plexins in adult brain have not been studied. Because their expression persists in the adult nervous system [34,37], and particularly given that Plexin-B proteins have the ability to link environmental cues to the regulation of RhoGTPases, we addressed the potential regulation of expression and function of neuronal Plexin-B proteins in mechanisms involved in memory. ...
... To generate mice lacking Plexin-B2 in forebrain-specific glutamatergic neurons, mice carrying a conditional allele for Plexin-B2 (PB2 fl/fl ) gene [24] were crossed with inducible CaMK-CreER T2 mice [38] induced twice per day i.p. with 50 mg/kg Tamoxifen over 5 consecutive days to obtain CaMK-CreER T2+ , PB2 −/− mice-mice of this genotype following Tamoxifen administration are referred to as CaMK-PB2 −/− mice in this manuscript. Mice expressing the ß-galactosidase (LacZ gene) under the control of plxnb2 and sema4c endogenous promoters (Plexin-B2-LacZ mice and Sema4C-LacZ mice, respectively) have been previously described [37,39,40] and previously validated in terms of faithful reproduction of expression patterns of the corresponding genes [34]. In both cases, the LacZ reporter is included in the targeted trap allele, and accordingly heterozygous knockout mice expressing LacZ were used here for expression analyses. ...
Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders.
... Plexin-B2 is a particularly strong candidate as a promoter of GBM invasion, as it was originally discovered due to its upregulation in brain cancers 18 , and subsequent analysis confirmed Plexin-B2 as a biomarker for malignant glioma based on patient data 19 . Fitting with a role in GBM invasion is also the fact that Plexin-B2 exerts a critical function in regulating neuroprecursor migration during brain development 20,21 . Our own studies have also revealed a link of high expression of Plexin-B2 with poor survival of GBM patients and that Plexin-B2 enhances the migratory capacity of GBM cells 22 . ...
... Note the striking differences in the growth/invasion patterns after 27 days: control cells invaded diffusively as individual cells (arrowheads), whereas PB2-KO GSCs invaded the surrounding matrix collectively as fasciculated migration streams (arrows). 20 . It is intriguing that Plexin-B2 functions to reduce cellular adhesion in the context of GBM invasion, as Plexins were originally described as homophilic adhesion molecules 52 , and in a neuroblastoma model, Plexin-As have been shown to act as proadhesion molecules 53 . ...
Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies establish Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness.
... Previously, we demonstrated a role of the transmembrane receptor Plexin-B2 (encoded by Plxnb2) during neuroprogenitor migration 9,10 . Plexins were originally identified as axon guidance molecules, but subsequently shown to also regulate cell migration and cytoskeletal dynamics through small GTPases during development and in adult physiology 11 . ...
Tissue repair after spinal cord injury requires the mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core, which is surrounded by an astrocytic border. Here we elucidate a temporally distinct gene signature in injury-activated microglia and macrophages (IAMs) that engages axon guidance pathways. Plexin-B2 is upregulated in IAMs and is required for motor sensory recovery after spinal cord injury. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAMs away from colliding cells and facilitates matrix compaction. Our data therefore establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAMs with the injury microenvironment during wound healing. Zhou et al. unveil a novel role for activated microglia and macrophages during wound healing after CNS injury. Microglia promote corralling and form a protective barrier at the injury penumbra via the axon guidance receptor Plexin-B2.
... Plexin-B2 is a member of B-class plexin axon guidance receptors that are activated by class 4 semaphorin ligands 8 . Plexin-B2 deletion in mice results in neural tube closure defect [9][10][11] . Plexin-B2 also regulates cerebellar granule cell migration, corticogenesis, as well as proliferation and migration of neuroblasts in postnatal rostral migratory stream 9,10,12,13 . ...
... Plexin-B2 deletion in mice results in neural tube closure defect [9][10][11] . Plexin-B2 also regulates cerebellar granule cell migration, corticogenesis, as well as proliferation and migration of neuroblasts in postnatal rostral migratory stream 9,10,12,13 . Besides neurodevelopment, plexins critically regulate cellular interactions in a wide range of contexts, including vascular development, immune system activation, bone homeostasis, as well as renal epithelial morphogenesis and repair [14][15][16][17][18][19][20][21][22][23] . ...
During multicellular organization, individual cells need to constantly respond to environmental cues and adjust contractile and adhesive forces in order to maintain tissue integrity. The signaling pathways linking biochemical cues and tissue mechanics are unclear. Here, we show that Plexin-B2 regulates mechanochemical integration during multicellular organization. In human embryonic stem cells (hESCs), Plexin-B2 controls cell shape and tissue geometry in both 2D epithelial colony and 3D spheroid aggregates by regulating actomyosin contractility and junctional/cell-matrix adhesive properties. Atomic force microscopy (AFM) directly demonstrates that Plexin-B2 modulates cell stiffness in hESC colonies, which in turn impacts cell proliferation and cell fate specification through b-catenin signaling and YAP mechanosensing. YAP also functions as a mechanoregulator downstream of Plexin-B2, thus forming a mechanochemical integrative loop. In human neuroprogenitor cells (hNPCs), Plexin-B2 similarly controls cell stiffness and tensile forces, as revealed by AFM and FRET tension sensor studies. Strikingly, Plexin- B2-deficient hNPCs display accelerated neuronal differentiation. From an organogenesis perspective, Plexin-B2 maintains cytoarchitectural integrity of neuroepithelium, as modeled in cerebral organoids. On a signaling level, Plexin-B2 engages extracellular as well as intracellular Ras-GAP and RBD domains for mechanoregulation through Rap and Rac GTPases. Our data unveil a fundamental function of Plexin-B2 for mechanochemical integration during multicellular organization, and shed light on the principle of force-mediated regulation of stem cell biology and tissue morphogenesis.
... Celle-ci agirait de façon non-cellulaire autonome via le récepteur Plexine-A2 (Kerjan et al., 2005;Renaud et al., 2008) sur le couplage noyau-centrosome, ce qui impacterait la migration de ces cellules (Renaud et al., 2008) (Figure 16). Si la Sema6A semble impliquée dans la migration, les Semaphorines 4C et 4G semblent, elles, importantes dans la prolifération et la différenciation des cellules granulaires du cerebellum, et ce via le récepteur Plexine-B2 (Friedel et al., 2007;Maier et al., 2011). Schéma du développement du cortex cérébelleux chez une souris sauvage et une souris déficiente en Sema6A. ...
Durant le développement, l’innervation d’une zone précise du cerveau par certaines branches axonales est un mécanisme encore mal compris. Afin d’aborder cette question, je me suis intéressée aux axones rétiniens qui innervent deux cibles principales du système visuel : le corps genouillé latéral dorsal (CGLd) et le colliculus supérieur. J’ai étudié le rôle de la protéine de guidage Sémaphorine 6D et de son récepteur Plexine-A1 dans l’innervation spécifique du CGLd par les axones rétiniens. J’ai ainsi découvert que chez les souris Sema6D-/- et Plexine-A1-/-, le tractus optique (formé par les axones rétiniens) entre dans le CGLd au lieu de le contourner et certains axones rétiniens innervent des régions ectopiques de l’autre côté du tractus optique. De plus, l’analyse des souris simple ou double hétérozygotes indique que ces deux protéines interagissent avec un mécanisme dose-dépendant. Grâce à des expériences de perte et de gain de fonction par électroporation rétinienne in utero, j’ai pu montrer la nécessité de Sema6D et de Plexine-A1 dans la rétine pour l’innervation des axones rétiniens et ce via des effets non cellulaire autonomes. Ces résultats révèlent un mécanisme dose-dépendant dans lequel Sema6D et PlexineA1 interagissent et assurent une communication axone-axone permettant l’innervation précise du CGLd par une sous-population d’axones rétiniens.
