scholarly journals The role of Robo receptors in cortical interneuron migration

2009 ◽  
Vol 3 ◽  
Author(s):  
Andrews William
Keyword(s):  
Cortical Interneuron ◽  
Robo Receptors

Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development

2021 ◽  
pp. ASN.2020111640
Author(s):  
Jinyu Li ◽  
Luiz Henrique Geraldo ◽  
Alexandre Dubrac ◽  
Georgia Zarkada ◽  
Anne Eichmann
Keyword(s):  
Kidney Diseases ◽  
Vascular Development ◽  
Content Type ◽  
Endothelial Proliferation ◽  
Robo Receptors ◽  
Glomerular Endothelium ◽  
Developing Kidney ◽  
Nephron Development ◽  
And Migration

BackgroundKidney function requires continuous blood filtration by glomerular capillaries. Disruption of glomerular vascular development or maintenance contributes to the pathogenesis of kidney diseases, but the signaling events regulating renal endothelium development remain incompletely understood. Here, we discovered a novel role of Slit2-Robo signaling in glomerular vascularization. Slit2 is a secreted polypeptide that binds to transmembrane Robo receptors and regulates axon guidance as well as ureteric bud branching and angiogenesis.MethodsWe performed Slit2-alkaline phosphatase binding to kidney cryosections from mice with or without tamoxifen-inducible Slit2 or Robo1 and -2 deletions, and we characterized the phenotypes using immunohistochemistry, electron microscopy, and functional intravenous dye perfusion analysis.ResultsOnly the glomerular endothelium, but no other renal endothelial compartment, responded to Slit2 in the developing kidney vasculature. Induced Slit2 gene deletion or Slit2 ligand trap at birth affected nephrogenesis and inhibited vascularization of developing glomeruli by reducing endothelial proliferation and migration, leading to defective cortical glomerular perfusion and abnormal podocyte differentiation. Global and endothelial-specific Robo deletion showed that both endothelial and epithelial Robo receptors contributed to glomerular vascularization.ConclusionsOur study provides new insights into the signaling pathways involved in glomerular vascular development and identifies Slit2 as a potential tool to enhance glomerular angiogenesis.

scholarly journals Morphogenesis of the islets of Langerhans is guided by extra-endocrine Slit2/3 signals

2020 ◽  
pp. MCB.00451-20
Author(s):  
Jennifer M. Gilbert ◽  
Melissa T. Adams ◽  
Nadav Sharon ◽  
Hariharan Jayaraaman ◽  
Barak Blum
Keyword(s):  
Axon Guidance ◽  
Islets Of Langerhans ◽  
Endocrine Cells ◽  
Β Cells ◽  
Robo Receptors ◽  
Correct Function ◽  
Cell Positioning ◽  
Spatial Architecture ◽  
Endocrine Tissues

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and non-endocrine tissues in late pancreas development. We show that function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the β-cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to β-cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

scholarly journals Activin receptor ALK4 coordinates extracellular signals and intrinsic transcriptional programs to regulate development of cortical somatostatin interneurons

2019 ◽  
Author(s):  
Christina Göngrich ◽  
Favio A. Krapacher ◽  
Hermany Munguba ◽  
Diana Fernández-Suárez ◽  
Annika Andersson ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Gene Promoter ◽  
Double Positive ◽  
Activin Receptor ◽  
Cortical Interneuron ◽  
Extracellular Signals ◽  
Inhibitory Circuitry ◽  
Cortical Interneurons ◽  
Interneuron Development

AbstractAlthough the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific loses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

scholarly journals Targeting the SLIT/ROBO pathway in tumor progression: molecular mechanisms and therapeutic perspectives

2019 ◽  
Vol 11 ◽  
pp. 175883591985523 ◽  
Author(s):  
Zhengdong Jiang ◽  
Gang Liang ◽  
Ying Xiao ◽  
Tao Qin ◽  
Xin Chen ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Tumor Development ◽  
Tumor Promotion ◽  
Cancer Therapies ◽  
Malignant Cells ◽  
Robo Receptors

The SLITs (SLIT1, SLIT2, and SLIT3) are a family of secreted proteins that mediate positional interactions between cells and their environment during development by signaling through ROBO receptors (ROBO1, ROBO2, ROBO3, and ROBO4). The SLIT/ROBO signaling pathway has been shown to participate in axonal repulsion, axon guidance, and neuronal migration in the nervous system and the formation of the vascular system. However, the role of the SLIT/ROBO pathway has not been thoroughly clarified in tumor development. The SLIT/ROBO pathway can produce both beneficial and detrimental effects in the growth of malignant cells. It has been confirmed that SLIT/ROBO play contradictory roles in tumorigenesis. Here, we discuss the tumor promotion and tumor suppression roles of the SLIT/ROBO pathway in tumor growth, angiogenesis, migration, and the tumor microenvironment. Understanding these roles will help us develop more effective cancer therapies.

scholarly journals Foxg1 Regulates the Postnatal Development of Cortical Interneurons

2018 ◽  
Vol 29 (4) ◽  
pp. 1547-1560 ◽  
Author(s):  
Wei Shen ◽  
Ru Ba ◽  
Yan Su ◽  
Yang Ni ◽  
Dongsheng Chen ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Neural Circuit ◽  
Neurological Diseases ◽  
Cortical Interneuron ◽  
Conditional Deletion ◽  
Cortical Interneurons ◽  
Migration Capacity ◽  
Dendritic Complexity ◽  
Foxg1 Syndrome

AbstractAbnormalities in cortical interneurons are closely associated with neurological diseases. Most patients with Foxg1 syndrome experience seizures, suggesting a possible role of Foxg1 in the cortical interneuron development. Here, by conditional deletion of Foxg1, which was achieved by crossing Foxg1fl/fl with the Gad2-CreER line, we found the postnatal distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex were impaired. Further investigations revealed an enhanced dendritic complexity and decreased migration capacity of Foxg1-deficient interneurons, accompanied by remarkable downregulation of Dlx1 and CXCR4. Overexpression of Dlx1 or knock down its downstream Pak3 rescued the differentiation detects, demonstrated that Foxg1 functioned upstream of Dlx1-Pak3 signal pathway to regulate the postnatal development of cortical interneurons. Due to the imbalanced neural circuit, Foxg1 mutants showed increased seizure susceptibility. These findings will improve our understanding of the postnatal development of interneurons and help to elucidate the mechanisms underlying seizure in patients carrying Foxg1 mutations.

ISDN2012_0271: The role of genetic programs and activity in the development of cortical interneuron diversity

2012 ◽  
Vol 30 (8) ◽  
pp. 636-636
Author(s):  
Gord Fishell ◽  
Natalia De Marco ◽  
Theofanis Karayannis ◽  
Renata Batista‐Brito ◽  
Jennifer Close ◽  
...  
Keyword(s):  
Cortical Interneuron

scholarly journals ALK4 coordinates extracellular and intrinsic signals to regulate development of cortical somatostatin interneurons

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Christina Göngrich ◽  
Favio A. Krapacher ◽  
Hermany Munguba ◽  
Diana Fernández-Suárez ◽  
Annika Andersson ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Gene Promoter ◽  
Double Positive ◽  
Intrinsic Signals ◽  
Cortical Interneuron ◽  
Extracellular Signals ◽  
Inhibitory Circuitry ◽  
Cortical Interneurons ◽  
Interneuron Development

Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific losses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

scholarly journals The Role of Redox Dysregulation in the Effects of Prenatal Stress on Embryonic Interneuron Migration

2019 ◽  
Vol 29 (12) ◽  
pp. 5116-5130 ◽  
Author(s):  
Jada Bittle ◽  
Edenia C Menezes ◽  
Michael L McCormick ◽  
Douglas R Spitz ◽  
Michael Dailey ◽  
...  
Keyword(s):  
Prenatal Stress ◽  
Restraint Stress ◽  
Time Lapse ◽  
Ganglionic Eminence ◽  
Cortical Interneuron ◽  
Redox Biology ◽  
Tangential Migration ◽  
Increased Risk ◽  
Induced Changes

Abstract Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and antioxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GAD67GFP+ interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence (GE), the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized DHE oxidation levels in GE and ameliorated the migration delay caused by prenatal stress. Through convergent redox manipula-tions, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development.

scholarly journals N-cadherin (Cdh2) Maintains Migration and Postmitotic Survival of Cortical Interneuron Precursors in a Cell-Type-Specific Manner

2019 ◽  
Vol 30 (3) ◽  
pp. 1318-1329
Author(s):  
Zsófia I László ◽  
Kinga Bercsényi ◽  
Mátyás Mayer ◽  
Kornél Lefkovics ◽  
Gábor Szabó ◽  
...  
Keyword(s):  
Target Selection ◽  
Cortical Plate ◽  
Specific Factor ◽  
Cell Type ◽  
Cortical Interneuron ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Interneuron Development

Abstract The multiplex role of cadherin-based adhesion complexes during development of pallial excitatory neurons has been thoroughly characterized. In contrast, much less is known about their function during interneuron development. Here, we report that conditional removal of N-cadherin (Cdh2) from postmitotic neuroblasts of the subpallium results in a decreased number of Gad65-GFP-positive interneurons in the adult cortex. We also found that interneuron precursor migration into the pallium was already delayed at E14. Using immunohistochemistry and TUNEL assay in the embryonic subpallium, we excluded decreased mitosis and elevated cell death as possible sources of this defect. Moreover, by analyzing the interneuron composition of the adult somatosensory cortex, we uncovered an unexpected interneuron-type-specific defect caused by Cdh2-loss. This was not due to a fate-switch between interneuron populations or altered target selection during migration. Instead, potentially due to the migration delay, part of the precursors failed to enter the cortical plate and consequently got eliminated at early postnatal stages. In summary, our results indicate that Cdh2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development. Furthermore, we also propose that unlike in pallial glutamatergic cells, Cdh2 is not universal, rather a cell type-specific factor during this process.

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