Role In Axon Guidance Research Articles

Analysis of Dip2B Expression in Adult Mouse Tissues Using the LacZ Reporter Gene.

Disconnected (disco)-interacting protein 2 homolog B (Dip2B) is a member of the Dip2 superfamily and plays an essential role in axonal outgrowth during embryogenesis. In adults, Dip2B is highly expressed in different brain regions, as shown by in situ analysis, and may have a role in axon guidance. However, the expression and biological role of Dip2B in other somatic tissues remain unknown. To better visualize Dip2B expression and to provide insight into the roles of Dip2B during postnatal development, we used a Dip2btm1a(wtsi)komp knock-in mouse model, in which a LacZ-Neo fusion protein is expressed under Dip2b promoter and allowed Dip2B expression to be analyzed by X-gal staining. qPCR analyses showed that Dip2b mRNA was expressed in a variety of somatic tissues, including lung and kidney, in addition to brain. LacZ staining indicated that Dip2B is broadly expressed in neuronal, reproductive, and vascular tissues as well as in the kidneys, heart, liver, and lungs. Moreover, neurons and epithelial cells showed rich staining. The broad and intense patterns of Dip2B expression in adult mice provide evidence of the distribution of Dip2B in multiple locations and, thereby, its implication in numerous physiological roles.

Distribution of planar cell polarity proteins in the developing avian retina

Planar cell polarity (PCP) is evolutionary conserved and play a critical role in proper tissue development and function. During central nervous system development, PCP proteins exhibit specific patterns of distribution and are indispensable for axonal growth, dendritogenesis, neuronal migration, and neuronal differentiation. The retina constitutes an excellent model in which to study molecular mechanisms involved in neural development. The analysis of the spatiotemporal expression of PCP proteins in this model constitutes an useful histological approach in order to identify possible roles of these proteins in retinogenesis. Immunohistochemical techniques revealed that Frz6, Celsr1, Vangl1, Pk1, Pk3, and Fat1 were present in emerging axons from recently differentiated ganglion cells in the chicken retina. Except for Vangl1, they were also asymmetrically distributed in differentiated amacrine cells. Pk1 and Pk3 were restricted in the outer nuclear layer to the outer segment of photoreceptors. Vangl1 was also located in the cell somata of Müller glia. Given these findings together, the distribution of PCP proteins in the developing chicken retina suggest essential roles in axonal guidance during early retinogenesis and a possible involvement in the establishment of cell asymmetry and maintenance of retinal cell phenotypes.

Neurologic Manifestations of COVID-19 in Children: Emerging Pathophysiologic Insights.

The COVID-19 pandemic has affected mortality and morbidity across all ages, including children. Neurologic manifestations of coronavirus disease 2019, ranging from headaches to cerebrovascular stroke, may involve the CNS or peripheral nervous system. Neurologic involvement is also noted in the multisystem inflammatory syndrome in children, a pediatric condition that occurs weeks after infection with severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19. Knowledge about mechanisms of neurologic disease and immunologic response to severe acute respiratory syndrome coronavirus 2 is scarce but rapidly growing. Here, we concisely review experimental and clinical data relevant to pathophysiologic hypotheses regarding neurologic manifestations of coronavirus disease 2019. We highlight important knowledge gaps in differences between adults and children in their response to coronavirus disease 2019.

Multi‐organ effects of SARS‐CoV2, more than a respiratory virus: effects on human astrocytes

The coronavirus disease‐2019 (COVID‐19) has led to one of the major outbreaks in modern history. The etiological agent of COVID‐19 is the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). SARS‐CoV‐2 infects the respiratory system's epithelial cells via the angiotensin‐converting enzyme 2 (ACE2) receptor, causing from non or mild symptoms to severe viral pneumonia, and in some cases, death. Based on evolving clinical evidence, it is now unfitting to label SARS‐CoV‐2 as just a respiratory virus, as lately, various reports substantiate its pathogenicity in other organs of the body, including the central nervous system (CNS). Despite conflicting results regarding ACE2 expression in brain tissue, the latest data show that ACE2 is robustly expressed by CNS cells, suggesting that CNS is a potential target for SARS‐CoV‐2 infection. Astrocytes are the most abundant glial cell type within the CNS and play a role in axon guidance and synaptic support, control the blood‐brain barrier flow, and regulate neuroinflammation. To test if SARS‐CoV‐2 can enter into the CNS via astrocytes and then elicit adverse neurological effects, we have initiated studies to test if astrocytes express ACE2 and whether SARS‐CoV‐2 can infect human astrocytes via this receptor. We have found that astrocytes robustly express ACE2 at the mRNA and protein levels. We are currently testing if astrocytes are susceptible to SARS‐CoV‐2 infection, which could subsequently lead to neuronal damage and possibly account for some of the neurological symptoms observed in COVID‐19 patients. We hope to contribute to gain insights into the mechanisms of SARS‐CoV‐2 infection in the CNS and its potential physiological effects with this work.

FGFR/Heartless and Smog interact synergistically to negatively regulate Fog mediated G-protein coupled receptor signaling in the Drosophila nervous system.

Folded gastrulation (Fog) is a secreted ligand that signals through the G-protein-coupled receptors Mist and Smog and the G-protein Concertina to activate downstream effectors to elicit cell-shape change during gastrulation. In the embryonic central nervous system (CNS), Fog has roles in axon guidance and glial morphogenesis. However, the elements of the pathway as well as mechanisms required for transducing the signal in this context have not been determined. We find that while Concertina is essential for Fog signaling, Mist is dispensable and Smog, surprisingly, functions as a negative regulator of the pathway in the CNS. Interestingly Heartless, a fibroblast growth factor receptor, also functions as a negative regulator. Furthermore, both Heartless and Smog interact in a synergistic manner to regulate Fog signaling. Our results thus identify Heartless and Smog as part of a common regulatory pathway that functions to restrict Fog signaling in the embryonic CNS and highlights the context-specific role for Fog receptors during development.

Endoglycan plays a role in axon guidance by modulating cell adhesion.

Axon navigation depends on the interactions between guidance molecules along the trajectory and specific receptors on the growth cone. However, our in vitro and in vivo studies on the role of Endoglycan demonstrate that in addition to specific guidance cue - receptor interactions, axon guidance depends on fine-tuning of cell-cell adhesion. Endoglycan, a sialomucin, plays a role in axon guidance in the central nervous system of chicken embryos, but it is neither an axon guidance cue nor a receptor. Rather, Endoglycan acts as a negative regulator of molecular interactions based on evidence from in vitro experiments demonstrating reduced adhesion of growth cones. In the absence of Endoglycan, commissural axons fail to properly navigate the midline of the spinal cord. Taken together, our in vivo and in vitro results support the hypothesis that Endoglycan acts as a negative regulator of cell-cell adhesion in commissural axon guidance.

EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis.

Endothelial tip cells are essential for VEGF‐induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial‐specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down‐regulated in EVL‐deficient P5‐retinal endothelial cells. Consistently, EVL deletion impairs VEGF‐induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor‐2 internalization and signaling.

The effect of brain-derived neurotrophic factor on motor development and its relation to the pattern of feeding in early infancy

Background Infant feeding is a modifiable health behavior that has long-term effect on various aspects of infant's neurodevelopmental achievement. Neurotrophins are a family of proteins, especially nerve growth factor and brain-derived neurotrophic factor (BDNF), that play a major role in the development, nutrition, growth, and maintenance of the neurons. Moreover, BDNF has a major role in axonal guidance, promoting growth of dendrites and dendritic spines, and in the pathogenesis of neurodegenerative, cardiometabolic, and autoimmune diseases. Aim This study aimed to evaluate the effect of feeding pattern in the first 6 months of life on BDNF serum level and motor development in early infancy. Patients and methods This cross-sectional study included 60 clinically healthy infants aged 6–12 months who were categorized according to their feeding pattern in the first 6 months of life into 30 breastfed and 30 formula-fed infants. BDNF serum levels were measured by enzyme-linked immunosorbent assay, and Denver developmental screening tests were assessed in relation to the feeding pattern. Results Infants with delayed achievement of motor milestones had significant lower level of BDNF than those with appropriate development. Breastfed infants had higher BDNF level (3.45±1.6 ng/ml) than formula-fed infants (1.98±1.30 ng/ml) (P<0.0001). Achievement of motor developmental milestone was significantly delayed in artificially fed than breastfed infant (43.3 vs. 16.7%) (P=0.02). Regression analysis demonstrated that BDNF is an independent predictor of motor development in early infancy. Conclusion BDNF is an important regulator of motor development in early infancy. Serum level of BDNF was higher; achievement of motor milestones was earlier in breastfed than formula-fed infants. Health programs encouraging exclusive breastfeeding in the first 6 months of life should be established. Efforts should be done to follow-up the motor development of artificially fed infant for early detection of any delay.

Roles of type IIa receptor protein tyrosine phosphatases as synaptic organizers.

Neurons establish circuits for brain functions such as cognition, emotion, learning, and memory. Their connections are mediated by synapses, which are specialized cell-cell adhesions responsible for neuronal signal transmission. During neurodevelopment, synapse formation is triggered by interactions of cell adhesion molecules termed synaptic organizers or synapse organizers. Type IIa receptor protein tyrosine phosphatases (IIa RPTPs; also known as leukocyte common antigen-related receptor tyrosine phosphatases or LAR-RPTPs) play important roles in axon guidance and neurite extension, and also serve as presynaptic organizers. IIa RPTPs transsynaptically interact with multiple sets of postsynaptic organizers, mostly in a splicing-dependent fashion. Here, we review and update research progress on IIa RPTPs, particularly regarding their functional roles in vivo demonstrated using conditional knockout approach and structural insights into their extracellular and intracellular molecular interactions revealed by crystallography and other biophysical techniques. Future directions in the research field of IIa RPTPs are also discussed, including recent findings of the molecular assembly mechanism underlying the formation of synapse-specific nanostructures essential for synaptic functions.

Pax6 modulates intra-retinal axon guidance and fasciculation of retinal ganglion cells during retinogenesis

Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master regulator gene, has a spatio-temporal expression typically restricted till neurogenesis and fate-specification. However, our observation of persistent expression of Pax6 in mature RGCs led us to hypothesize that Pax6 could play a major role in axon guidance after fate specification. Here, we found significant alteration in intra-retinal axon guidance and fasciculation upon knocking out of Pax6 in E15.5 retina. Through unbiased transcriptome profiling between Pax6fl/fl and Pax6−/− retinas, we revealed the mechanistic insight of its role in axon guidance. Our results showed a significant increase in the expression of extracellular matrix molecules and decreased expression of retinal fate specification and neuron projection guidance molecules. Additionally, we found that EphB1 and Sema5B are directly regulated by Pax6 owing to the guidance defects and improper fasciculation of axons. We conclude that Pax6 expression post fate specification of RGCs is necessary for regulating the expression of axon guidance genes and most importantly for maintaining a conducive ECM through which the nascent axons get guided and fasciculate to reach the optic disc.

Collapsin Response Mediator Proteins: Novel Targets for Alzheimer's Disease.

Numerous experimental and postmortem studies have increasingly reported dystrophic axons and dendrites, and alterations of dendritic spine morphology and density in the hippocampus as prominent changes in the early stages of Alzheimer's disease (AD). Furthermore, these alterations tend to correlate well with the progressive cognitive decline observed in AD. For these reasons, and because these neurite structures have a capacity to re-grow, re-establish lost connections, and are critical for learning and memory, there is compelling evidence to suggest that therapeutic interventions aimed at preventing their degradation or promoting their regrowth may hold tremendous promise in preventing the progression of AD. In this regard, collapsin response mediator proteins (CRMPs), a family of phosphoproteins playing a major role in axon guidance and dendritic growth, are especially interesting. The roles these proteins play in neurons and immune cells are reviewed here.

Improved β-catenin detection in spinal cord tissue sections: autofluorescence quenching

Experimental studies on spinal cord regeneration are focusing on the windows of opportunity to improve spinal cord microenvironment via spinal-centric repair pathways. One pathway of particular interest is the Wnt/β-catenin signalling pathway which plays a vital role in axonal guidance, synaptic assembly and function, neuronal survival and connectivity after spinal cord trauma to induce repair. Upregulation of β-catenin expression is often taken as evidence of regeneration mechanisms through the Wnt/ β-catenin pathway. However, these studies may not have optimised the staining protocol for β-catenin to enable accurate detection of the protein. Given possible issues with the background or endogenous tissue autofluorescence, there is a need to optimise the protocol further to allow better visualisation of β-catenin. So far, there are no studies which report optimising spinal cord tissues for β-catenin to reduce autofluorescence, and as β-catenin is widely used in spinal cord injury (SCI) and other spinal cord tissue studies, thus it is an important issue to address. To achieve reliable detection and localisation of β-catenin, we utilised sequential quenching techniques using 1% NaBH4 and 1mM CuSO4 in 50mM ammonium acetate buffer to reduce both background and fixative-induced autofluorescence. Our results showed that sequential autofluorescence quenching is crucial in β-catenin detection, and this improved technique indicates that β-catenin is localised in the spinal cord white matter regions. Objective approach for the β-catenin localisation is highly significant as it unravelled an objective identification and illuminate the pattern of distribution of β-catenin for researcher focusing on spinal cord repair studies via the Wnt/β-catenin pathway following SCI.

PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses

SummaryLeukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. In the current study, we analyzed the synaptic role of PTPσ using newly generated, single conditional knockout (cKO) mice targeting PTPσ. We found that the number of synapses was reduced in PTPσ cKO cultured neurons in association with impaired excitatory synaptic transmission, abnormal vesicle localization, and abnormal synaptic ultrastructure. Strikingly, loss of presynaptic PTPσ reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. Furthermore, loss of presynaptic PTPσ in hippocampal CA1 pyramidal neurons had no impact on postsynaptic glutamate receptor responses in subicular pyramidal neurons. Postsynaptic PTPσ deletion had no effect on excitatory synaptic strength. Taken together, these results demonstrate that PTPσ is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.

The first quarter of the C-terminal domain of Abelson regulates the WAVE regulatory complex and Enabled in axon guidance

BackgroundAbelson tyrosine kinase (Abl) plays a key role in axon guidance in linking guidance receptors to actin dynamics. The long C-terminal domain (CTD) of Drosophila Abl is important for this role, and previous work identified the ‘first quarter’ (1Q) of the CTD as essential. Here, we link the physical interactions of 1Q binding partners to Abl’s function in axon guidance.MethodsProtein binding partners of 1Q were identified by GST pulldown and mass spectrometry, and validated using axon guidance assays in the embryonic nerve cord and motoneurons. The role of 1Q was assessed genetically, utilizing a battery of Abl transgenes in combination with mutation or overexpression of the genes of pulled down proteins, and their partners in actin dynamics. The set of Abl transgenes had the following regions deleted: all of 1Q, each half of 1Q (‘eighths’, 1E and 2E) or a PxxP motif in 2E, which may bind SH3 domains.ResultsGST pulldown identified Hem and Sra-1 as binding partners of 1Q, and our genetic analyses show that both proteins function with Abl in axon guidance, with Sra-1 likely interacting with 1Q. As Hem and Sra-1 are part of the actin-polymerizing WAVE regulatory complex (WRC), we extended our analyses to Abi and Trio, which interact with Abl and WRC members. Overall, the 1Q region (and especially 2E and its PxxP motif) are important for Abl’s ability to work with WRC in axon guidance. These areas are also important for Abl’s ability to function with the actin regulator Enabled. In comparison, 1E contributes to Abl function with the WRC at the midline, but less so with Enabled.ConclusionsThe 1Q region, and especially the 2E region with its PxxP motif, links Abl with the WRC, its regulators Trio and Abi, and the actin regulator Ena. Removing 1E has specific effects suggesting it may help modulate Abl’s interaction with the WRC or Ena. Thus, the 1Q region of Abl plays a key role in regulating actin dynamics during axon guidance.

Neuropilin-1 Expression on CD4 T Cells Is Atherogenic and Facilitates T Cell Migration to the Aorta in Atherosclerosis.

Neuropilin 1 (Nrp1) is a type I transmembrane protein that plays important roles in axonal guidance, neuronal development, and angiogenesis. Nrp1 also helps migrate thymus-derived regulatory T cells to vascular endothelial growth factor (VEGF)-producing tumors. However, little is known about the role of Nrp1 on CD4 T cells in atherosclerosis. In ApoE-/- mice fed a Western diet for 15 wk, we found a 2-fold increase in Nrp1+Foxp3- CD4 T cells in their spleens, periaortic lymph nodes, and aortas, compared with chow-fed mice. Nrp1+Foxp3- CD4 T cells had higher proliferation potential, expressed higher levels of the memory marker CD44, and produced more IFN-γ when compared with Nrp1- CD4 T cells. Treatment of CD4 T cells with oxLDL increased Nrp1 expression. Furthermore, atherosclerosis-susceptible mice selectively deficient for Nrp1 expression on T cells developed less atherosclerosis than their Nrp1-sufficient counterparts. Mechanistically, we found that CD4 T cells that express Nrp1 have an increased capacity to migrate to the aorta and periaortic lymph nodes compared to Nrp1- T cells, suggesting that the expression of Nrp1 facilitates the recruitment of CD4 T cells into the aorta where they can be pathogenic. Thus, we have identified a novel role of Nrp1 on CD4 T cells in atherosclerosis. These results suggest that manipulation of Nrp1 expression on T cells can affect the outcome of atherosclerosis and lower disease incidence.

Semaphorin 5A suppresses the proliferation and migration of lung adenocarcinoma cells.

Semaphorin 5A (SEMA5A), a member of the semaphorin family, plays an important role in axonal guidance. Previously, the authors identified another possible role of SEMA5A as a prognostic biomarker for non-smoking women with lung adenocarcinoma in Taiwan, and this phenomenon has been validated in other ethnic groups. However, the functional significance of SEMA5A in lung adenocarcinoma remains unclear. Therefore, we assessed the function of SEMA5A in three lung adenocarcinoma cell lines in this study. Kaplan-Meier Plotter for lung cancer was conducted for survival analyses. Reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis were performed to investigate the expression and post-translational regulation of SEMA5A in lung adenocar-cinoma cell lines. A pre-designed PyroMark CpG assay and 5-aza-2′-deoxycytidine treatment were used to measure the methylation levels of SEMA5A. The biological functions of lung adenocarcinoma cells overexpressing SEMA5A were investigated by microarrays, and validated both in vitro (proliferation, colony formation and migration assays) and in vivo (tumor xenografts) experiments. The results revealed that the hypermethylation of SEMA5A and the cleavage of the extracellular domain of SEMA5A were responsible for the downregulation of the SEMA5A levels in lung adenocarcinoma cells (A549 and H1299) as compared to the normal controls. Functional analysis of SEMA5A-regulated genes revealed that they were involved in cellular growth and proliferation. The overexpression of SEMA5A in A549 and H1299 cells significantly decreased the proliferation (P<0.01), colony formation (P<0.001) and migratory ability (P<0.01) of the cells. The suppressive effects of SEMA5A on the proliferative and migratory ability of the cells were also observed in both in vitro and in vivo experiments using brain metastatic Bm7 lung adenocarcinoma cells. On the whole, the findings of this study suggest a suppressive role for SEMA5A in lung adenocarcinoma involving the inhibition of the proliferation and migration of lung transformed cells.

Lowering EphA4 Does Not Ameliorate Disease in a Mouse Model for Severe Spinal Muscular Atrophy.

EphA4 is a receptor of the Eph-ephrin system, which plays an important role in axon guidance during development. Previously, we identified EphA4 as a genetic modifier of amyotrophic lateral sclerosis (ALS) in both zebrafish and rodent models, via modulation of the intrinsic vulnerability, and re-sprouting capacity of motor neurons. Moreover, loss of EphA4 rescued the motor axon phenotype in a zebrafish model of spinal muscular atrophy (SMA). Similar to ALS, SMA is a neurodegenerative disorder affecting spinal motor neurons resulting in neuromuscular junction (NMJ) denervation, muscle atrophy and paralysis. In this study, we investigated the disease modifying potential of reduced EphA4 protein levels in the SMNΔ7 mouse model for severe SMA. Reduction of EphA4 did not improve motor function, survival, motor neuron survival or NMJ innervation. Our data suggest that either lowering EphA4 has limited therapeutic potential in SMA or that the clinical severity hampers the potential beneficial role of EphA4 reduction in this mouse model for SMA.

Inhibition of Rho GTPases in Invertebrate Growth Cones Induces a Switch in Responsiveness to Retinoic Acid.

During development, growth cones are essential for axon pathfinding by sensing numerous guidance cues in their environment. Retinoic acid, the metabolite of vitamin A, is important for neurite outgrowth during vertebrate development, but may also play a role in axon guidance, though little is known of the cellular mechanisms involved. Our previous studies showed that retinoid-induced growth cone turning of invertebrate motorneurons requires local protein synthesis and calcium influx. However, the signalling pathways that link calcium influx to cytoskeletal dynamics involved in retinoid-mediated growth cone turning are not currently known. The Rho GTPases, Cdc42 and Rac, are known regulators of the growth cone cytoskeleton. Here, we demonstrated that inhibition of Cdc42 or Rac not only prevented growth cone turning toward retinoic acid but could also induce a switch in growth cone responsiveness to chemorepulsion or growth cone collapse. However, the effects of Cdc42 or Rac inhibition on growth cone responsiveness differed, depending on whether the turning was induced by the all-trans or 9-cis retinoid isomer. The effects also differed depending on whether the growth cones maintained communication with the cell body. These data strongly suggest that Cdc42 and Rac are downstream effectors of retinoic acid during growth cone guidance.

PlexinA1 is crucial for the midline crossing of callosal axons during corpus callosum development in BALB/cAJ mice.

The corpus callosum (CC) is the biggest commissure that links cerebral hemispheres. Guidepost structures develop in the cortical midline during CC development and express axon guidance molecules that instruct neurons regarding the proper direction of axonal elongation toward and across the cortical midline. Neuropilin-1 (Npn1), a high affinity receptor for class 3 semaphorins (Sema3s) localized on cingulate pioneering axons, plays a crucial role in axon guidance to the midline through interactions with Sema3s. However, it remains unclear which type of Plexin is a component of Sema3 holoreceptors with Npn1 during the guidance of cingulate pioneering axons. To address the role of PlexinA1 in CC development, we examined with immunohistochemistry the localization of PlexinA1, Npn1, and Sema3s using embryonic brains from wild-type (WT) and PlexinA1-deficient (PlexinA1 knock-out (KO)) mice with a BALB/cAJ background. The immunohistochemistry confirmed the expression of PlexinA1 in callosal axons derived from the cingulate and neocortex of the WT mice on embryonic day 17.5 (E17.5) but not in the PlexinA1 KO mice. To examine the role of PlexinA1 in the navigation of callosal axons, the extension of callosal axons toward and across the midline was traced in brains of WT and PlexinA1 KO mice at E17.5. As a result, callosal axons in the PlexinA1 KO brains had a significantly lower incidence of midline crossing at E17.5 compared with the WT brains. To further examine the role of PlexinA1 in CC development, the CC phenotype was examined in PlexinA1 KO mice at postnatal day 0.5 (P0.5). Most of the PlexinA1 KO mice at P0.5 showed agenesis of the CC. These results indicate the crucial involvement of PlexinA1 in the midline crossing of callosal axons during CC development in BALB/cAJ mice.

Mouse Models Shed Light on the SLIT/ROBO Pathway in Pancreatic Development and Cancer

The SLIT/ROBO pathway is classically known for its role in axon guidance, and is frequently lost in pancreatic cancer, but the biology behind this is poorly understood. Two recent articles (Nat. Commun. 2018;9:5082; Nat. Commun. 2018;9:5083) using mouse models show that SLIT/ROBO signaling is crucial to determine pancreatic cell identity during development and suppresses the stromal activation in disease, through divergent mechanisms. SLIT/ROBO proteins thus link development and cancer, but appear to have distinct functions in health and disease.