Abstract:Netrin-1 regulates cell migration and adhesion during the development of the nervous system, vasculature, lung, pancreas, muscle, and mammary gland. It is also proposed to function as a dependence ligand that inhibits apoptosis; however, studies disagree regarding whether netrin-1 loss-of-function mice exhibit increased cell death. Furthermore, previously studied netrin-1 loss-of-function gene-trap mice express a netrin-1-β-galactosidase protein chimera with potential for toxic gain-of-function effects, as wel… Show more
“…The delay is less severe in Robo3 KOs than in Dcc KOs, consistent with previous observations in commissural axonal outgrowth [18]. Ntn1 KO, on the other hand, caused a more severe defect than Dcc KO, also consistent with previous observations in axon guidance [21, 25]. This is likely due to the fact that another homologue of DCC, the Neogenin (Neo1) receptor, has some redundant function and thus could compensate for the loss of DCC [24].…”
Section: Resultssupporting
confidence: 91%
“…5). Ntn1 KOs were also reported to have a normal number of spinal cord neurons at E11.5 and E13.5 [21, 25]. Therefore, the loss of Ntn1 , Dcc, or Robo3 does not affect neurogenesis, either.Fig.…”
BackgroundNewborn neurons often migrate before undergoing final differentiation, extending neurites, and forming synaptic connections. Therefore, neuronal migration is crucial for establishing neural circuitry during development. In the developing spinal cord, neuroprogenitors first undergo radial migration within the ventricular zone. Differentiated neurons continue to migrate tangentially before reaching the final positions. The molecular pathways that regulate these migration processes remain largely unknown. Our previous study suggests that the DCC receptor is important for the migration of the dorsal spinal cord progenitors and interneurons. In this study, we determined the involvement of the Netrin1 ligand and the ROBO3 coreceptor in the migration.ResultsBy pulse labeling neuroprogenitors with electroporation, we examined their radial migration in Netrin1 (Ntn1), Dcc, and Robo3 knockout mice. We found that all three mutants exhibit delayed migration. Furthermore, using immunohistochemistry of the BARHL2 interneuron marker, we found that the mediolateral and dorsoventral migration of differentiated dorsal interneurons is also delayed. Together, our results suggest that Netrin1/DCC signaling induce neuronal migration in the dorsal spinal cord.ConclusionsNetrin1, DCC, and ROBO3 have been extensively studied for their functions in regulating axon guidance in the spinal commissural interneurons. We reveal that during earlier development of dorsal interneurons including commissural neurons, these molecules play an important role in promoting cell migration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0074-x) contains supplementary material, which is available to authorized users.
“…The delay is less severe in Robo3 KOs than in Dcc KOs, consistent with previous observations in commissural axonal outgrowth [18]. Ntn1 KO, on the other hand, caused a more severe defect than Dcc KO, also consistent with previous observations in axon guidance [21, 25]. This is likely due to the fact that another homologue of DCC, the Neogenin (Neo1) receptor, has some redundant function and thus could compensate for the loss of DCC [24].…”
Section: Resultssupporting
confidence: 91%
“…5). Ntn1 KOs were also reported to have a normal number of spinal cord neurons at E11.5 and E13.5 [21, 25]. Therefore, the loss of Ntn1 , Dcc, or Robo3 does not affect neurogenesis, either.Fig.…”
BackgroundNewborn neurons often migrate before undergoing final differentiation, extending neurites, and forming synaptic connections. Therefore, neuronal migration is crucial for establishing neural circuitry during development. In the developing spinal cord, neuroprogenitors first undergo radial migration within the ventricular zone. Differentiated neurons continue to migrate tangentially before reaching the final positions. The molecular pathways that regulate these migration processes remain largely unknown. Our previous study suggests that the DCC receptor is important for the migration of the dorsal spinal cord progenitors and interneurons. In this study, we determined the involvement of the Netrin1 ligand and the ROBO3 coreceptor in the migration.ResultsBy pulse labeling neuroprogenitors with electroporation, we examined their radial migration in Netrin1 (Ntn1), Dcc, and Robo3 knockout mice. We found that all three mutants exhibit delayed migration. Furthermore, using immunohistochemistry of the BARHL2 interneuron marker, we found that the mediolateral and dorsoventral migration of differentiated dorsal interneurons is also delayed. Together, our results suggest that Netrin1/DCC signaling induce neuronal migration in the dorsal spinal cord.ConclusionsNetrin1, DCC, and ROBO3 have been extensively studied for their functions in regulating axon guidance in the spinal commissural interneurons. We reveal that during earlier development of dorsal interneurons including commissural neurons, these molecules play an important role in promoting cell migration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0074-x) contains supplementary material, which is available to authorized users.
“…Previous studies suggested that TRIM9 was expressed in the hippocampus, although RNA probe and antibody specificity were not confirmed in Trim9 Ϫ/Ϫ samples (Li et al, 2001;Berti et al, 2002;Tanji et al, 2010). We reported the generation of a conditional Trim9 allele (Trim9 fl ) and germline deletion of murine Trim9 using CMV-Cre Trim9 Ϫ/Ϫ (Winkle et al, 2014).…”
Section: Trim9 Is Expressed In the Embryonic And Adult Murine Hippocamentioning
confidence: 99%
“…TRIM9 is an evolutionarily conserved member of the TRIpartite Motif (TRIM) family of ubiquitin ligases (Berti et al, 2002;Tanji et al, 2010). We recently identified TRIM9 as a regulator of neuronal morphogenesis in cortical neurons (Winkle et al, 2014;Menon et al, 2015).…”
During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9 Ϫ/Ϫ adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9 Ϫ/Ϫ mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors.
“…Recently, the generation of floxed mice [18] has allowed researchers to bypass this issue and expand novel roles for these cues at the cellular and tissue-specific level which will be further developed below.…”
Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions.
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