Expression patterns of semaphorin7A and plexinC1during rat neural development suggest roles in axon guidance and neuronal migration
© Pasterkamp et al; licensee BioMed Central Ltd. 2007
Received: 24 April 2007
Accepted: 29 August 2007
Published: 29 August 2007
Although originally identified as embryonic axon guidance cues, semaphorins are now known to regulate multiple, distinct, processes crucial for neuronal network formation including axon growth and branching, dendritic morphology, and neuronal migration. Semaphorin7A (Sema7A), the only glycosylphosphatidylinositol-anchored semaphorin, promotes axon growth in vitro and is required for the proper growth of the mouse lateral olfactory tract in vivo. Sema7A has been postulated to signal through two unrelated receptors, an RGD-dependent α1β1-integrin and a member of the plexin family, plexinC1. β1-integrins underlie Sema7A-mediated axon growth and Sema7A function in the immune system. Sema7A-plexinC1 interactions have also been implicated in immune system function, but the neuronal role of this ligand-receptor pair remains to be explored. To gain further insight into the function(s) of Sema7A and plexinC1 during neural development, we present here a detailed analysis of Sema7A and plexinC1 expression in the developing rat nervous system.
In situ hybridization revealed select expression of Sema7A and plexinC1 in multiple neuronal systems including: the olfactory system, the hypothalamo-hypophysial system, the hippocampus, the meso-diencephalic dopamine system, and the spinal cord. Within these systems, Sema7A and plexinC1 are often expressed in specific neuronal subsets. In general, Sema7A transcript levels increase significantly towards adulthood, whereas plexinC1 expression decreases as development proceeds.
PlexinC1, but not Sema7A, is strongly expressed by distinct populations of migrating neurons. In addition to neuronal expression, Sema7A and plexinC1 transcripts were detected in oligodendrocytes and ependymal cells, respectively.
Sema7A and plexinC1 expression patterns are consistent with these proteins serving both cooperative and separate functions during neural development. The prominent expression of plexinC1 in several distinct populations of migrating neurons suggests a novel role for this plexin family member in neuronal migration.
The formation of neural circuits during development depends on a precise series of molecular and cellular events. Once neurons have migrated to their final destination, they elaborate axons and dendrites along predetermined routes in the developing embryo to establish highly specific connections with their targets. Semaphorins, a large family of secreted and membrane-associated proteins, are instrumental in establishing patterns of neuronal connectivity and influence many different aspects of neuronal network formation including axonal and dendritic growth, branching, guidance and pruning, target recognition, and synapse formation . Significant progress has been made in understanding how semaphorins provide guidance for extending neurites. Their contribution to other aspects of neuronal network formation is, however, less well understood. For example, in addition to their chemotropic effects, semaphorins can exert neurite growth promoting effects . For example, both in vitro and in vivo semaphorin7A (Sema7A, also known as CDw108) functions as an axon growth-promoting factor . Sema7A is the only glycosylphosphatidylinositol (GPI)-anchored semaphorin described to date, and it was first identified as a member of the semaphorin family in a search for vertebrate orthologues of class 8 viral semaphorins [3, 4]. In addition to promoting neurite outgrowth, Sema7A expression and function studies support it playing a role in immune system function and bone morphogenesis. In the immune system, Sema7A is expressed in the lymphoid and myeloid lineages and is known to affect several immunological functions including immune cell proliferation, chemotaxis and cytokine release . Furthermore, Sema7A defines the John-Milton-Hagen human blood group on erythrocytes, which is implicated in the pathogenesis of a clinically benign autoimmune disorder . A role for Sema7A in bone formation is supported by the observation that Sema7A can regulate osteoclast differentiation and pre-osteoblastic cell migration in vitro . In line with this observation, polymorphisms in the human SEMA7A gene were recently found to be associated with bone mineral density and fracture risk in postmenopausal women .
Studies of Sema7A expression and function in chick and mouse embryos define multiple, distinct, roles for Sema7A in the developing nervous system. Sema7A expression during early chick embryonic development hints at its involvement in neural crest cell migration and/or differentiation . At later developmental stages, when neuronal connections are being established and remodelled, Sema7A promotes growth and branching of certain neurite subsets [2, 10]. For example, Sema7A enhances the neurite outgrowth of cultured cortical, olfactory and sensory, but not vomeronasal, neurons. In support of these observations, Sema7A-/- mice show marked defects in the growth of olfactory bulb axons projecting through the lateral olfactory tract during development .
Members of the plexin family are the major semaphorin receptors in the nervous system and Sema7A has been shown to bind to one of the nine vertebrate plexins, plexinC1, in vitro . Surprisingly, the axon growth promoting effects of Sema7A do not require plexinC1 but instead depend on β1-integrins and associated signalling cascades . However, the ability of Sema7A to bind plexinC1, the implication of Sema7A-plexinC1 signaling in immune system function, and the expression of the genes encoding both proteins at times when select neuronal connections are established [2, 4, 11–15], suggests that Sema7A-plexinC1 interactions participate in neuronal network formation. Unfortunately, the distribution of Sema7A and plexinC1 during late embryonic and postnatal neural development, when important events in neuronal network formation and remodelling occur, is not well characterized. As a step toward obtaining a better understanding of the separate and cooperative functions of Sema7A and plexinC1 during neural development, we have determined the spatiotemporal expression patterns of Sema7A and plexinC1 in the developing and adult rat nervous system.
Sema7A and plexinC1are differentially expressed during neural development
To further determine the spatial and temporal distributions of Sema7A and plexinC1, we performed in situ hybridization analyses on tissue sections of the embryonic, postnatal and mature rat nervous system. Staining was absent from control sections, which were processed with sense probes [see Additional file 1]. In support of our Northern and RT-PCR data (Fig. 1), in situ hybridization revealed that Sema7A levels increase towards adulthood, whereas plexinC1 signals generally decline. For our expression studies, we largely focused on the olfactory system, hypothalamus and pituitary, hippocampus, meso-diencephalic dopamine (mdDA) system, and spinal cord, all of which display distinguishing features of Sema7A and plexinC1 expression.
PlexinC1 and Sema7Aexpression in the hypothalamo-hypophysial system
Once LHRH neurons reach their final destination in the CNS they project axons to the median eminence (ME), where LHRH is deposited into the hypothalamo-hypophysial portal system to stimulate LH release from the anterior pituitary . During development, the ME strongly expresses plexinC1 and to a lesser extent Sema7A (Fig. 3J, K). In addition to the ME, other portions of the developing hypothalamic area, including the supraoptic nucleus (SON), display prominent Sema7A and plexinC1 expression (Fig. 3A, B). As hypothalamic development progresses, plexinC1 expression becomes largely confined to the paraventricular nucleus (PVN), whereas Sema7A transcripts remain widely distributed throughout the hypothalamus (Fig. 3C). In contrast to LHRH axons, which terminate at the ME, fibers of magnocellular PVN and SON neurons pass through the ME to innervate the neural lobe of the pituitary . Similar to LHRH projections to the median eminence, both developing PVN and SON projection neurons along with their target structure, the neural lobe of the pituitary, display strong plexinC1 expression during development (Fig. 3B, E, G, H).
These observations are in line with a recent study showing that plexinC1 is expressed in magnocellular PVN and SON neurons at E12.5 and E15.5 .
The pituitary consists of three lobes; the neural lobe, the intermediate lobe, and the anterior lobe. The neural lobe derives from diencephalic tissue and the anterior and intermediate lobes form from an invagination of the oral ectoderm called Rathke's pouch . During pituitary development, expression of Sema7A is most pronounced in Rathke's pouch, and at later developmental stages in the intermediate and anterior lobes (Fig. 3D, F). In contrast, plexinC1 is largely confined to the neural part of the pituitary, with only weak expression observed in the intermediate lobe at late embryonic, but not postnatal or adult, stages (Fig. 3E, G, H, I). Overall, these Sema7A and plexinC1 expression patterns are consistent with Sema7A and plexinC1 playing prominent roles in neuronal migration and network formation in the hypothalamo-hypophysial system.
Sema7A and plexinC1expression in the olfactory system
Hippocampal CA2 neurons express high levels of Sema7A
Sema7A and plexinC1define subsets of meso-diencephalic dopamine neurons
Differential expression of Sema7A and plexinC1in the spinal cord, DRG and in muscle
The GPI-linked semaphorin Sema7A was originally identified as a vertebrate homologue of a viral semaphorin [3, 4]. Besides regulating aspects of immune system function and bone morphogenesis, Sema7A is a potent growth-stimulating factor for embryonic axons and postnatal dendrites [2, 10]. Plexins are the predominant semaphorin receptors and, not surprisingly, Sema7A binds one of the nine vertebrate plexins, plexinC1 . However, the axon growth-promoting effects of Sema7A do not rely on plexinC1 but instead require β1-integrins . This is intriguing since plexinC1 and Sema7A transcripts are concomitantly expressed at the time neuronal connections are established and remodelled [2, 4, 12, 13]. To better comprehend the neuronal function(s) of Sema7A and plexinC1 and to assess a potential role for neuronal Sema7A-plexinC1 signalling, we performed a detailed comparative analysis of Sema7A and plexinC1 expression patterns. The gene expression patterns reported here are consistent with both separate and cooperative Sema7A and plexinC1 functions.
PlexinC1 is expressed in migrating neurons
In addition to their role as axonal repellents and attractants, semaphorins can also guide migrating cells through repulsive or attractive mechanisms. For example, secreted class 3 semaphorins (Sema3s) influence the migration of GABAergic interneurons from the medial ganglionic eminence and restrict the migration of trunk neural crest cells to the anterior sclerotome [25, 26]. Similarly, class 6 transmembrane semaphorins (Sema6s) influence granule cell migration in the cerebellum and regulate the migration of endothelial and myocardial cells in the developing chick heart [27–29]. In many instances, these effects on migration require plexins. For example, plexinA1 mediates Sema6D-dependent migration events during cardiac morphogenesis and Sema3E-mediated somatic vascular patterning is dependent on plexinD1 [28, 30]. In line with these observations, we find prominent plexinC1 expression in several classes of migratory neurons, including LHRH neurons in the nasal region, cells in the SVZ and RMS, and cells in the rhombic lip and external granule cell layer (EGL) [see Additional file 2]. These results suggest a novel role for plexinC1 in neuronal cell migration.
In the adult, LHRH regulates the release of anterior pituitary gonadotropes and is essential for reproduction. LHRH neurons originate from the embryonic nasal placode and migrate to the hypothalamus along olfactory/vomeronasal nerves. Several factors influence LHRH neuron migration, either directly or indirectly via the extension and guidance of vomeronasal axons, including growth factors (e.g. hepatocyte growth factor (HGF)) and axon guidance molecules (e.g. netrin-1) [20, 31, 32]. The plexinC1 expression patterns we report here are consistent with both direct and indirect effects on LHRH neuron migration. PlexinC1 could affect migrating LHRH neurons directly by mediating their selective adhesion to vomeronasal fibers or by influencing their subsequent migration. This would require LHRH cell-surface plexinC1 to bind membrane-associated proteins on vomeronasal axons. Interestingly, the only mammalian plexinC1 ligand identified to date, Sema7A, is expressed in embryonic and postnatal vomeronasal neurons. Alternatively, plexinC1 could act in a homophilic manner. This idea is supported by the ability of plexins to engage in homophilic interactions [33, 34] and by the expression of plexinC1 in migrating LHRH neurons and vomeronasal neurons. A direct effect of plexinC1 on migrating neurons is further supported by recent work showing that plexinC1 is required for the proper allocation of developing magnocellular neurons to the PVN and SON, presumably by interacting with a repulsive ligand in the anterior hypothalamus . Instead of affecting the migration of LHRH neurons directly, however, plexinC1 may influence vomeronasal/olfactory projections. The genetic ablation of guidance receptors such as DCC and neuropilin-2 results in severe defects in vomeronasal connectivity and as a result in misrouting of migrating LHRH neurons [35, 36]. However, further work is needed to assess whether plexinC1, by analogy with other plexins, acts as a bona fide guidance or growth receptor. The finding that Sema7A does not affect vomeronasal axon growth and guidance in vitro  argues against a role for this potential plexinC1 ligand in the formation of vomeronasal nerve branches.
In addition to LHRH neurons, plexinC1 is expressed in SVZ/RMS cells and in the EGL of the developing cerebellum. The migration of neuroblasts in the RMS, and their subsequent differentiation into olfactory bulb granule and periglomerular cells is controlled by a complex molecular program which includes multiple growth and guidance molecules . On basis of their expression in and around the SVZ, RMS, and throughout the olfactory system, semaphorins and their receptors likely contribute to the molecular control of RMS neuroblast migration and/or differentiation. The robust expression of Sema7A in the OB and in tissues surrounding the RMS is especially intriguing because of the expression of two distinct Sema7A (co)receptors in cells in the RMS: plexinC1 and β1 integrins . β1 integrins are required for RMS cell chain formation and for the maintenance of glial tubes within the RMS. Although these morphological effects have been ascribed to distinct laminin isoforms, Sema7A shares at least one integrin receptor with laminins . While the function of plexinC1 in the RMS remains to be addressed, cerebellar granule cells comprise another population of migrating neurons that expresses both plexinC1 and β1 integrins. Following their generation in the rhombic lip, cerebellar granule cell precursors migrate tangentially over the cerebellar plate to form the EGL. This initial migration is followed by a series of profound morphological changes and subsequent inward migration of postmitotic granule cells into the internal granular layer . Inactivation of β1 integrins results in cerebellar granule cell precursor proliferation defects and in the disruption of cerebellar folia. These defects have been attributed to perturbed interactions between a sonic hedgehog-laminin protein complex and α6β1 or α7β1 integrins [41, 42]. In immune cells α1β1, but not α6β1, mediates Sema7A function in monocyte activation, however, the role of α7β1 has not been addressed . Instead of binding to β1 integrins on GCPs, however, Sema7A may bind plexinC1, which is enriched in cells in the rhombic lip and EGL. In addition to Sema7A, several other semaphorins are expressed in the developing cerebellum [27, 43]. It is becoming clear that individual plexins can interact with members of different semaphorin classes. For example, plexinD1 can bind Sema3E and Sema4A, while plexinAs bind Sema6s and Sema3s, the latter via neuropilins [44, 45]. Therefore, reassessing the semaphorin binding partners of plexinC1 may help to further define the role of this protein in neuronal cell migration and also in other biological processes.
Sema7A and plexinC1 are expressed in specific subsets of neurons and glial cells
Neurons have often been grouped on basis of neurotransmitter expression or anatomical location. It is becoming increasingly clear, however, that within these chemically or anatomically defined neural systems distinct neuronal subsets exist, each displaying unique molecular and functional characteristics. For example, only a small subset of dopaminergic neurons in the SNc were recently found to express the netrin-1 receptor DCC and to specifically innervate the most dorsal aspect of the SNc projection area, the striatum . As we report here, Sema7A and plexinC1 label subsets of neurons in several different systems including the olfactory system, cortex, hippocampus, mdDA system and neuromuscular system.
In the postnatal and adult hippocampus, Sema7A transcripts are enriched in the CA2 subfield. CA2 pyramidal neurons give rise to divergent intrahippocampal projections while receiving a prominent input from the mammillary nucleus . Sema7A, plexinC1 and α1β1 integrins are expressed in the hippocampus and mammillary nucleus [47–49] suggesting that Sema7A signalling may influence the formation and maintenance of CA2 afferent and efferent projections. Another hallmark of CA2 pyramidal neurons is their relative resistance to cell death during temporal lobe epilepsy [50, 51]. The observation that Sema7A acts as a survival factor for embryonic chick DRG neurons in vitro (R.J. Pasterkamp and A.L. Kolodkin, unpublished observations), together with its prominent expression in CA2 pyramidal neurons and epilepsy-induced (re-)expression of α1β1 integrins in hippocampal neurons and astrocytes [49, 52], suggests that Sema7A might protect CA2 neurons against epileptic damage.
In the mdDA system Sema7A labels a subpopulation of SNc neurons, whereas plexinC1 is expressed by mdDA neurons in the central VTA. This observation is in line with a comparative analysis of gene expression profiles between the SN and VTA, reporting highest levels of Sema7A in mdDA neurons of the SN and of plexinC1 in the VTA . Based on the expression of Sema7A and plexinC1 in the prefrontal cortex and striatum, it is tempting to speculate that these molecules contribute to the formation and maintenance of efferent and afferent dopaminergic midbrain connections.
Is plexinC1 a Sema7A receptor?
Many semaphorin-mediated biological effects rely on receptor complexes that contain plexins as obligatory binding and/or signal transducing subunits. Sema7A binds plexinC1 , but thus far no functional role has been attributed to this interaction in neurons. Instead, the specific Sema7A functions in the neural and immune systems described to date require β1 integrins and not plexinC1 [2, 39]. However, the ability of Sema7A and plexinC1 to physically interact with high affinity, together with their neuronal expression profiles, supports the notion that cooperative interactions between these proteins play some role during neural development. These expression data presented here show that plexinC1 frequently labels projection neurons, e.g. mdDA neurons in the VTA or sensory neurons in the OE, while the putative plexinC1 ligand Sema7A is present in their target structures, i.e. the prefrontal cortex and OB, respectively. While these observations are consistent with cooperative ligand-receptor interactions, it is evident that Sema7A and plexinC1 also function independently. For example, Sema7A is widely expressed in the adult nervous system, but plexinC1 expression is limited to only a few adult neural structures. In contrast, plexinC1 is expressed at high levels during early neural development, but mid-embryonic Sema7A expression is relatively weak. Overall, these observations indicate that additional interaction partners likely exist for Sema7A and plexinC1. Interestingly, α1 and β1 integrin subunits are expressed in the adult nervous system [48, 54], while numerous other semaphorins, most of which have not yet been evaluated for plexinC1 binding, are present in the early embryonic nervous system (e.g. [55–57]). Furthermore, and in striking contrast to Sema7A, both plexinC1 and the β1 integrin subunit show a highly specific and spatially restricted expression patterns in the adult nervous system. This suggests that other Sema7A receptors may exist in addition to plexinC1 and β1 integrins.
The Sema7A and plexinC1 expression patterns reported in this study are consistent with both cooperative and separate functions for the proteins encoded by these genes during neural development. Cooperative effects are supported by complementary expression patterns in various neuronal systems. Separate functions are strongly suggested at early and late stages of development, when either plexinC1 or Sema7A is prominently expressed. This suggests there are additional binding partners for plexinC1 and Sema7A. For plexinC1 these may include semaphorins belonging to other subclasses, and Sema7A already has been shown to signal through α1β1 integrins. The expression of plexinC1 in several groups of migratory neurons suggests a novel role for this plexin family member in cell migration. Future work will address these and other plexinC1 and Sema7A biological functions.
All animal procedures were conducted in strict compliance with approved institutional protocols. Timed-pregnant Wistar (Harlan CPB, Zeist, The Netherlands) were killed by intraperitoneal injection of a lethal dose of Euthesate (Ceva Sante Animale) and decapitated. Embryos were rapidly removed via cesarean section. The day of the vaginal plug was considered embryonic day (E)0.5. E14, E15, E16, E18, and E19 embryos were covered with Tissue-Tek (Sakura), and quickly frozen in dry ice-cooled 2-methylbutane (Sigma-Aldrich). At least five animals were processed for each stage. The day of birth was designated postnatal day (P)0. P0, P5, P14, and P15 rat pups and adult rats (2–4 months) were anesthetized and quickly decapitated. Neural tissues (brain, spinal cord, and dorsal root ganglia (DRG)) were dissected out and frozen in dry-ice cooled 2-methylbutane. Consecutive coronal, horizontal, and sagittal sections (10–20 μm) were cut on a cryostat and stored at -80°C until use.
Northern blot analysis
Northern blot analysis was performed as described before . In brief, RNA samples (40 μg) prepared from E19 and adult rat brain using TRIzol reagent (GibcoBRL) were size separated by electrophoresis in a 0.8% formaldehyde gel, transferred to a positively charged nylon membrane (Hybond-N+; Amersham Biosciences), and UV-crosslinked. DNA probes were labelled with [32P]-dCTP (Amersham Pharmacia Biotech) using the Prime-It II random labelling kit (Stratagene) and membranes were hybridized following standard procedures. A 362 base pair rat Sema7A cDNA probe was used to detect Sema7A . Following detection of Sema7A, membranes were reprobed twice, first for plexinC1 using a 921 base pair cDNA probe (base pairs 3601–4522 of the mouse plexinC1 coding region), and then for GAPDH . The Sema7A and plexinC1 probes do not cross-hybridize with the mRNA of other semaphorins and plexins, respectively.
Total RNA was isolated from E15, E19, P0, P14 or adult brain using TRIzol reagent (GibcoBRL). RT-PCR was performed as described before using primers specific for Sema7A, plexinC1 or GAPDH, as a control . PCR conditions were as follows: 5 min/95°C, 30 s/95°C, 30 s/57°C, 45 s/72°C (27 cycles), 7 min/72°C. The following forward and reverse primers were used: mouse Sema7A; 5'-tgctggaacttggtgaatga-3' and 5'-atcttgcagccgattgaagt-3' (product size is 465 bp), mouse plexinC1; 5'-tggtggtgacgaggtacaaa-3' and 5'-tactgcactgctccatcagg-3' (468 bp), and rat GAPDH; 5'-ctcatgaccacagtccatgc-3' and 5'-atgtaggccatgaggtccac-3' (473 bp). The PCR products were run in an agarose gel and visualized with ethidium bromide. PCR amplification specificity was confirmed by sequencing.
In situ hybridization
Although antibodies have been raised against mouse Sema7A and plexinC1 [16, 17], these are not suitable for immunohistochemical detection of these proteins in analyses of the nervous system (R.J.P. and A.L.K., unpublished observations). Therefore we used in situ hybridization to study the distribution of Sema7A and plexinC1 in tissue sections. Non-radioactive in situ hybridization was performed using alkali-hydrolyzed digoxigenin-labelled cRNA probes transcribed from rat Sema7A (a 362 base pair fragment corresponding to nucleotides 364–726 of coding region) , mouse plexinC1 (a ~2.25 kb fragment encoded by EST AA940270) , or rat tyrosine hydroxylase (TH; basepair 915–1137 of the coding region)  cDNAs. The generation of cRNA probes and the in situ hybridization procedure were as described previously . Sections subjected to the entire in situ hybridization procedure, but with no probe or sense probe added, exhibited no specific hybridization signal [see Additional file 1] . The specificity of the in situ hybridization procedure was also inferred from the clearly distinct distribution patterns of Sema7A, plexinC1 and TH. In addition, we have performed experiments using a mouse Sema7A probe . The expression patterns obtained with rat and mouse probes were identical.
Immunohistochemistry was performed on cryosections as described previously . In brief, sections were fixed for 1h at room temperature (RT), washed three times in Tris-buffered saline containing 0.2% TritonX-100 (TBS-T), blocked in TBS-T containing 0.2% bovine serum albumin (BSA) for 2h at RT, and incubated with primary antibodies overnight at 4°C. LHRH was detected with polyclonal rabbit antibodies (SW-1; 1:5000, a kind gift from Dr. S. Wray, National Institutes of Health, MD)  and α-MSH was detected with polyclonal rabbit antibodies (1:1000, a kind gift from Dr. F.W. van Leeuwen, University of Maastricht, The Netherlands) . All primary antisera were diluted in TBS-T containing 0.2% BSA. No immunostaining was detected in control sections in which the primary antibodies were replaced by TBS-T. After three washes in TBS, sections were incubated with biotinylated goat anti-rabbit (1:100), all diluted in TBS-T containing 0.2% BSA, for 1 hr at RT. Then, sections were washed three times in TBS and incubated with avidin-biotin-peroxidase complex (Vectastain ABC kit; Vector Laboratories) in TBS containing 0.25% gelatin and 0.5% Triton X-100 for 1 hr at RT. After two washes in TBS and a brief wash in 50 mM Tris-HCl, pH 7.6, sections were reacted with a solution containing 0.035% DAB and 0.015% hydrogen peroxide in 50 mM Tris-HCl for 15 min at RT. The reaction was terminated by several washes in 50 mM Tris-HCl and sections were mounted in glycerol. Combined in situ hybridization for Sema7A or plexinC1 and immunohistochemistry for TH was performed as described previously  using polyclonal rabbit TH antibodies (1:1000, Pel-Freez).
We thank members of the Kolodkin and Pasterkamp laboratories for helpful discussions; Peter Burbach for reading the manuscript; Susan Wray for her gift of the anti-LHRH antibody; Fred van Leeuwen for his gift of the α-MSH antibody; Peter Burbach, Marten Smidt and Simone Smits for their gift of the rat TH probe template and fruitful discussions. This work is supported by grants from the Netherlands Organization of Scientific Research and Dutch Brain Foundation (to RJP and SMK), the International Parkinson Foundation, the Human Frontier Science Program and ABC Genomics Center Utrecht (to RJP), and NINDS/NIH (to ALK). RJP is a NARSAD Henry and William Test Investigator, and ALK is an investigator of the Howard Hughes Medical Institute.
- Yazdani U, Terman JR: The semaphorins. Genome Biol. 2006, 7: 211-PubMed CentralView ArticlePubMedGoogle Scholar
- Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL: Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature. 2003, 424: 398-405.View ArticlePubMedGoogle Scholar
- Lange C, Liehr T, Goen M, Gebhart E, Fleckenstein B, Ensser A: New eukaryotic semaphorins with close homology to semaphorins of DNA viruses. Genomics. 1998, 51: 340-50.View ArticlePubMedGoogle Scholar
- Xu X, Ng S, Wu ZL, Nguyen D, Homburger S, Seidel-Dugan C, Ebens A, Luo Y: Human semaphorin K1 is glycosylphosphatidylinositol-linked and defines a new subfamily of viral-related semaphorins. J Biol Chem. 1998, 273: 22428-34.View ArticlePubMedGoogle Scholar
- Kikutani H, Suzuki K, Kumanogoh A: Immune semaphorins: increasing members and their diverse roles. Adv Immunol. 2007, 93: 121-43.View ArticlePubMedGoogle Scholar
- Seltsam A, Strigens S, Levene C, Yahalom V, Moulds M, Moulds JJ, Hustinx H, Weisbach V, Figueroa D, Bade-Doeding C, et al: The molecular diversity of Sema7A, the semaphorin that carries the JMH blood group antigens. Transfusion. 2007, 47: 133-46.View ArticlePubMedGoogle Scholar
- Delorme G, Saltel F, Bonnelye E, Jurdic P, Machuca-Gayet I: Expression and function of semaphorin 7A in bone cells. Biol Cell. 2005, 97: 589-97.View ArticlePubMedGoogle Scholar
- Koh JM, Oh B, Lee JY, Lee JK, Kimm K, Kim GS, Park BL, Cheong HS, Shin HD, Hong JM, et al: Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women. J Hum Genet. 2006, 51: 112-7.View ArticlePubMedGoogle Scholar
- Bao ZZ, Jin Z: Sema3D and Sema7A have distinct expression patterns in chick embryonic development. Dev Dyn. 2006, 235: 2282-9.PubMed CentralView ArticlePubMedGoogle Scholar
- Moresco EM, Donaldson S, Williamson A, Koleske AJ: Integrin-mediated dendrite branch maintenance requires Abelson (Abl) family kinases. J Neurosci. 2005, 25: 6105-18.View ArticlePubMedGoogle Scholar
- Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, et al: Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell. 1999, 99: 71-80.View ArticlePubMedGoogle Scholar
- Mauti O, Sadhu R, Gemayel J, Gesemann M, Stoeckli ET: Expression patterns of plexins and neuropilins are consistent with cooperative and separate functions during neural development. BMC Dev Biol. 2006, 6: 32-PubMed CentralView ArticlePubMedGoogle Scholar
- Perala NM, Immonen T, Sariola H: The expression of plexins during mouse embryogenesis. Gene Expr Patterns. 2005, 5: 355-62.View ArticlePubMedGoogle Scholar
- Xu C, Fan CM: Allocation of paraventricular and supraoptic neurons requires Sim1 function: a role for a Sim1 downstream gene PlexinC1. Mol Endocrinol. 2007Google Scholar
- Walzer T, Galibert L, De Smedt T: Dendritic cell function in mice lacking Plexin C1. Int Immunol. 2005, 17: 943-50.View ArticlePubMedGoogle Scholar
- Comeau MR, Johnson R, DuBose RF, Petersen M, Gearing P, VandenBos T, Park L, Farrah T, Buller RM, Cohen JI, et al: A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR. Immunity. 1998, 8: 473-82.View ArticlePubMedGoogle Scholar
- Mine T, Harada K, Matsumoto T, Yamana H, Shirouzu K, Itoh K, Yamada A: CDw108 expression during T-cell development. Tissue Antigens. 2000, 55: 429-36.View ArticlePubMedGoogle Scholar
- Schwanzel-Fukuda M, Pfaff DW: Origin of luteinizing hormone-releasing hormone neurons. Nature. 1989, 338: 161-4.View ArticlePubMedGoogle Scholar
- Wray S, Nieburgs A, Elkabes S: Spatiotemporal cell expression of luteinizing hormone-releasing hormone in the prenatal mouse: evidence for an embryonic origin in the olfactory placode. Brain Res Dev Brain Res. 1989, 46: 309-18.View ArticlePubMedGoogle Scholar
- Tobet SA, Schwarting GA: Minireview: recent progress in gonadotropin-releasing hormone neuronal migration. Endocrinology. 2006, 147: 1159-65.View ArticlePubMedGoogle Scholar
- King JC, Tobet SA, Snavely FL, Arimura AA: LHRH immunopositive cells and their projections to the median eminence and organum vasculosum of the lamina terminalis. J Comp Neurol. 1982, 209: 287-300.View ArticlePubMedGoogle Scholar
- Armstrong WE: Hypothalamic Supraoptic and paraventricular nuclei. The rat nervous system. 1995, 377-390. secondGoogle Scholar
- Amaral DG, Witter MP: Hippocampal formation. The rat nervous system. 1995, 443-493. secondGoogle Scholar
- Smidt MP, Burbach JP: How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci. 2007, 8: 21-32.View ArticlePubMedGoogle Scholar
- Gammill LS, Gonzalez C, Gu C, Bronner-Fraser M: Guidance of trunk neural crest migration requires neuropilin 2/semaphorin 3F signaling. Development. 2006, 133: 99-106.View ArticlePubMedGoogle Scholar
- Marin O, Yaron A, Bagri A, Tessier-Lavigne M, Rubenstein JL: Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science. 2001, 293: 872-5.View ArticlePubMedGoogle Scholar
- Kerjan G, Dolan J, Haumaitre C, Schneider-Maunoury S, Fujisawa H, Mitchell KJ, Chedotal A: The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nat Neurosci. 2005, 8: 1516-24.View ArticlePubMedGoogle Scholar
- Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J, Aoki K, Yabuki M, Hori M, Fujisawa H, et al: Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev. 2004, 18: 435-47.PubMed CentralView ArticlePubMedGoogle Scholar
- Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Yabuki M, Harada K, Hori M, Kikutani H: Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol. 2004, 6: 1204-11.View ArticlePubMedGoogle Scholar
- Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD: Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science. 2005, 307: 265-8.View ArticlePubMedGoogle Scholar
- Giacobini P, Messina A, Wray S, Giampietro C, Crepaldi T, Carmeliet P, Fasolo A: Hepatocyte growth factor acts as a motogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration. J Neurosci. 2007, 27: 431-45.View ArticlePubMedGoogle Scholar
- Schwarting GA, Raitcheva D, Bless EP, Ackerman SL, Tobet S: Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons. Eur J Neurosci. 2004, 19: 11-20.View ArticlePubMedGoogle Scholar
- Ohta K, Mizutani A, Kawakami A, Murakami Y, Kasuya Y, Takagi S, Tanaka H, Fujisawa H: Plexin: a novel neuronal cell surface molecule that mediates cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Neuron. 1995, 14: 1189-99.View ArticlePubMedGoogle Scholar
- Hartwig C, Veske A, Krejcova S, Rosenberger G, Finckh U: Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin. BMC Neurosci. 2005, 6: 53-PubMed CentralView ArticlePubMedGoogle Scholar
- Schwarting GA, Kostek C, Bless EP, Ahmad N, Tobet SA: Deleted in colorectal cancer (DCC) regulates the migration of luteinizing hormone-releasing hormone neurons to the basal forebrain. J Neurosci. 2001, 21: 911-9.PubMedGoogle Scholar
- Cariboni A, Hickok J, Rakic S, Andrews W, Maggi R, Tischkau S, Parnavelas JG: Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci. 2007, 27: 2387-95.View ArticlePubMedGoogle Scholar
- Murase S, Horwitz AF: Directions in cell migration along the rostral migratory stream: the pathway for migration in the brain. Curr Top Dev Biol. 2004, 61: 135-52.View ArticlePubMedGoogle Scholar
- Belvindrah R, Hankel S, Walker J, Patton BL, Muller U: Beta1 integrins control the formation of cell chains in the adult rostral migratory stream. J Neurosci. 2007, 27: 2704-17.View ArticlePubMedGoogle Scholar
- Suzuki K, Okuno T, Yamamoto M, Pasterkamp RJ, Takegahara N, Takamatsu H, Kitao T, Takagi J, Rennert PD, Kolodkin AL, et al: Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature. 2007, 446: 680-684.View ArticlePubMedGoogle Scholar
- Yacubova E, Komuro H: Cellular and molecular mechanisms of cerebellar granule cell migration. Cell Biochem Biophys. 2003, 37: 213-34.View ArticlePubMedGoogle Scholar
- Graus-Porta D, Blaess S, Senften M, Littlewood-Evans A, Damsky C, Huang Z, Orban P, Klein R, Schittny JC, Muller U: Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron. 2001, 31: 367-79.View ArticlePubMedGoogle Scholar
- Blaess S, Graus-Porta D, Belvindrah R, Radakovits R, Pons S, Littlewood-Evans A, Senften M, Guo H, Li Y, Miner JH, et al: Beta1-integrins are critical for cerebellar granule cell precursor proliferation. J Neurosci. 2004, 24: 3402-12.PubMed CentralView ArticlePubMedGoogle Scholar
- Rabacchi SA, Solowska JM, Kruk B, Luo Y, Raper JA, Baird DH: Collapsin-1/semaphorin-III/D is regulated developmentally in Purkinje cells and collapses pontocerebellar mossy fiber neuronal growth cones. J Neurosci. 1999, 19: 4437-48.PubMedGoogle Scholar
- Kruger RP, Aurandt J, Guan KL: Semaphorins command cells to move. Nat Rev Mol Cell Biol. 2005, 6: 789-800.View ArticlePubMedGoogle Scholar
- Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh A, Hori M: Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. Embo J. 2007, 26: 1373-84.PubMed CentralView ArticlePubMedGoogle Scholar
- Osborne PB, Halliday GM, Cooper HM, Keast JR: Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents. Neuroscience. 2005, 131: 671-81.View ArticlePubMedGoogle Scholar
- Anderson KL, Ferreira A: alpha1 Integrin activation: a link between beta-amyloid deposition and neuronal death in aging hippocampal neurons. J Neurosci Res. 2004, 75: 688-97.View ArticlePubMedGoogle Scholar
- Grooms SY, Terracio L, Jones LS: Anatomical localization of beta 1 integrin-like immunoreactivity in rat brain. Exp Neurol. 1993, 122: 253-9.View ArticlePubMedGoogle Scholar
- Pinkstaff JK, Lynch G, Gall CM: Localization and seizure-regulation of integrin beta 1 mRNA in adult rat brain. Brain Res Mol Brain Res. 1998, 55: 265-76.View ArticlePubMedGoogle Scholar
- Babb TL, Brown WJ, Pretorius J, Davenport C, Lieb JP, Crandall PH: Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia. 1984, 25: 729-40.View ArticlePubMedGoogle Scholar
- Sloviter RS: "Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res Bull. 1983, 10: 675-97.View ArticlePubMedGoogle Scholar
- Fasen K, Elger CE, Lie AA: Distribution of alpha and beta integrin subunits in the adult rat hippocampus after pilocarpine-induced neuronal cell loss, axonal reorganization and reactive astrogliosis. Acta Neuropathol (Berl). 2003, 106: 319-22.View ArticleGoogle Scholar
- Chung CY, Seo H, Sonntag KC, Brooks A, Lin L, Isacson O: Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet. 2005, 14: 1709-25.PubMed CentralView ArticlePubMedGoogle Scholar
- Murase S, Hayashi Y: Integrin alpha1 localization in murine central and peripheral nervous system. J Comp Neurol. 1998, 395: 161-76.View ArticlePubMedGoogle Scholar
- Giger RJ, Wolfer DP, De Wit GMJ, Verhaagen J: Anatomy of rat semaphorin III/collapsin-1 mRNA expression and relationship to developing nerve tracts during neuroembryogenesis. J Comp Neurol. 1996, 375: 378-392.View ArticlePubMedGoogle Scholar
- Puschel AW, Adams RH, Betz H: The sensory innervation of the mouse spinal cord may be patterned by differential expression of and differential responsiveness to semaphorins. Mol Cell Neurosci. 1996, 7: 419-431.View ArticlePubMedGoogle Scholar
- Skaliora I, Singer W, Betz H, Puschel AW: Differential patterns of semaphorin expression in the developing rat brain. Eur J Neurosci. 1998, 10: 1215-1229.View ArticlePubMedGoogle Scholar
- Pasterkamp RJ, Dai HN, Terman JR, Wahlin KJ, Kim B, Bregman BS, Popovich PG, Kolodkin AL: MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat. Mol Cell Neurosci. 2005Google Scholar
- Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP: A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci. 2000, 3: 337-41.View ArticlePubMedGoogle Scholar
- Pasterkamp RJ, Giger RJ, Ruitenberger MJ, Holtmaat AJ, De Wit J, De Winter F, Verhaagen J: Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol Cell Neurosci. 1999, 13: 143-166.View ArticlePubMedGoogle Scholar
- Wray S, Gahwiler BH, Gainer H: Slice cultures of LHRH neurons in the presence and absence of brainstem and pituitary. Peptides. 1988, 9: 1151-75.View ArticlePubMedGoogle Scholar
- van Leeuwen FW, de Raay C, Swaab DF, Fisser B: The localization of oxytocin, vasopressin, somatostatin and luteinizing hormone releasing hormone in the rat neurohypophysis. Cell Tissue Res. 1979, 202: 189-201.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.