Slit2 and Robo3 modulate the migration of GnRH-secreting neurons

Gonadotropin-releasing hormone (GnRH) neurons are born in the nasal placode and migrate along olfactory and vomeronasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated by Slit2 and Robo3, members of the axon guidance Slit ligand and Robo receptor families. Mice lacking Slit2 or Robo3 have a reduced number of GnRH neurons in the forebrain, but a normal complement of their supporting axons, pointing to a direct role for these molecules in GnRH neuron migration.     

神经细胞迁移导向的分子机制

自１９世纪以来的研究表明,在胚胎发育期间和出生后,包括人在内的哺乳动物神经系统的大部分神经细胞（也许是所有神经细胞）都要经过一定距离的多运动才能抵达它们发挥功能的部位。这些细胞如何知道往哪个方向迁移呢？我们在分子水平对这个问题进行了研究。１９９９年发表的结果给出这样一个答案：脑内存在导向性分子,可以指导神经细胞的迁移方向,具体的发现是：一个叫Ｓｌｉｔ的分泌性蛋白南,对神经细胞有性作用,它的浓度梯度     

Growth and guidance cues for regenerating axons: where have they gone?

Both attractive and repellent cues are required to guide developing axons to their targets in the central nervous system. Critical guidance molecules in the developing brain include the semaphorins, netrins, slits, and ephrins. Current research indicates that many of these molecules and their receptors are expressed in the adult central nervous system (CNS), and that injury can alter the levels of these ligands/receptors. Recent studies have begun the process of elucidating the functions of these receptors in adult mammals, and the effects that they have on the regeneration of adult neurons. This review addresses our current knowledge with respect to the response of adult CNS neurons to axonal injury, interventions for enhancing the survival and regeneration of injured neurons, and the expression of developmental axon guidance cues in the injured mature CNS, with specific focus on the retino-tectal projection.     

The olfactory signal transduction for attractive odorants in Caenorhabditis elegans

Olfaction in Caenorhabditis elegans is a versatile and sensitive strategy to seek food and avoid danger by sensing volatile chemicals emitted by the targets. The ability to sense attractive odor is mainly accomplished by the AWA and AWC neurons. Previous studies have shown the components of the olfaction signal pathway in these two amphid chemosensory neurons, but integration of the individual signaling components requires further elucidation. Here we review the progresses in our understanding of signal pathways for attractive olfaction involving AWA and AWC neurons, and discuss how the different signal molecules might employ the common molecular cascades to transduce the olfactory system and guide behavior in each neuron.     

Attachment to an endogenous laminin-like protein initiates sprouting by leech neurons

Leech neurons in culture sprout rapidly when attached to extracts from connective tissue surrounding the nervous system. Laminin-like molecules that promote sprouting have now been isolated from this extracellular matrix. Two mAbs have been prepared that react on immunoblots with a approximately equal to 220- and a approximately equal to 340-kD polypeptide, respectively. These antibodies have been used to purify molecules with cross-shaped structures in the electron microscope. The molecules, of approximately equal to 10(3) kD on nonreducing SDS gels, have subunits of approximately equal to 340, 220, and 160-180 kD. Attachment to the laminin-like molecules was sufficient to initiate sprouting by single isolated leech neurons in defined medium. This demonstrates directly a function for a laminin-related invertebrate protein. The mAbs directed against the approximately equal to 220-kD chains of the laminin-like leech molecule labeled basement membrane extracellular matrix in leech ganglia and nerves. A polyclonal antiserum against the approximately equal to 220-kD polypeptide inhibited neurite outgrowth. Vertebrate laminin did not mediate the sprouting of leech neurons; similarly, the leech molecule was an inert substrate for vertebrate neurons. Although some traits of structure, function, and distribution are conserved between vertebrate laminin and the invertebrate molecule, our results suggest that the functional domains differ.     

The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans

Three known genes guide circumferential migrations of pioneer axons and mesodermal cells on the nematode body wall. unc-5 affects dorsal migrations, unc-40 primarily affects ventral migrations, and unc-6 affects migrations in both directions. Circumferential movements still occur, but are misdirected whereas longitudinal movements are normal in these mutants. Pioneer growth cones migrating directly on the epidermis are affected; growth cones migrating along established axon fascicles are normal. Thus these genes affect cell guidance and not cell motility per se. We propose that two opposite, adhesive gradients guide circumferential migrations on the epidermis. unc-5, unc-6, and unc-40 may encode these adhesion molecules or their cellular receptors. Neurons have access to the basal lamina and the basolateral surfaces of the epidermis, but mesodermal cells contact only the basal lamina. These genes probably identify molecular cues on the basal lamina that guide mesodermal migrations. The same basal lamina cues, or perhaps related molecules on the epidermal cell surfaces, guide pioneer neurons.     

Multiple Wnts and frizzled receptors regulate anteriorly directed cell and growth cone migrations in Caenorhabditis elegans

A set of conserved molecules guides axons along the metazoan dorsal-ventral axis. Recently, Wnt glycoproteins have been shown to guide axons along the anterior-posterior (A/P) axis of the mammalian spinal cord. Here, we show that, in the nematode Caenorhabditis elegans, multiple Wnts and Frizzled receptors regulate the anterior migrations of neurons and growth cones. Three Wnts are expressed in the tail, and at least one of these, EGL-20, functions as a repellent. We show that the MIG-1 Frizzled receptor acts in the neurons and growth cones to promote their migrations and provide genetic evidence that the Frizzleds MIG-1 and MOM-5 mediate the repulsive effects of EGL-20. While these receptors mediate the effects of EGL-20, we find that the Frizzled receptor LIN-17 can antagonize MIG-1 signaling. Our results indicate that Wnts play a key role in A/P guidance in C. elegans and employ distinct mechanisms to regulate different migrations.     

BMP type I receptor complexes have distinct activities mediating cell fate and axon guidance decisions

The finding that morphogens, signalling molecules that specify cell identity, also act as axon guidance molecules has raised the possibility that the mechanisms that establish neural cell fate are also used to assemble neuronal circuits. It remains unresolved, however, how cells differentially transduce the cell fate specification and guidance activities of morphogens. To address this question, we have examined the mechanism by which the Bone morphogenetic proteins (BMPs) guide commissural axons in the developing spinal cord. In contrast to studies that have suggested that morphogens direct axon guidance decisions using non-canonical signal transduction factors, our results indicate that canonical components of the BMP signalling pathway, the type I BMP receptors (BMPRs), are both necessary and sufficient to specify the fate of commissural neurons and guide their axonal projections. However, whereas the induction of cell fate is a shared property of both type I BMPRs, axon guidance is chiefly mediated by only one of the type I BMPRs, BMPRIB. Taken together, these results indicate that the diverse activities of BMP morphogens can be accounted for by the differential use of distinct components of the canonical BMPR complex.     

Trying to understand axonal regeneration in the CNS of fish.

In contrast to the situation in mammals and birds, neurons in the central nervous system (CNS) of fish--such as the retinal ganglion cells--are capable of regenerating their axons and restoring vision. Special properties of the glial cells and the neurons of the fish visual pathway appear to contribute to the success of axonal regeneration. The fish oligodendrocytes lack the axon growth inhibiting molecules that interfere with axonal extension in mammals. Instead, fish optic nerve oligodendrocytes support--at least in vitro--axonal elongation of fish as well as that of rat retinal axons. Moreover, the fish retinal ganglion cells re-express upon injury a set of growth-associated cell surface molecules and equip the regenerating axons throughout their path and up into their target, the tectum opticum with these molecules. This may indicate that the injured fish ganglion cells reactivate the cellular machinery necessary for axonal regrowth and pathfinding. Furthermore, the target itself provides positional marker molecules even in adult fish. These marker molecules are required to guide the regenerating axons back to their retinotopic home territory within the tectum.     

The hector G-protein coupled receptor is required in a subset of fruitless neurons for male courtship behavior

Male courtship behavior in Drosophila melanogaster is controlled by two main regulators, fruitless (fru) and doublesex (dsx). Their sex-specific expression in brain neurons has been characterized in detail, but little is known about the downstream targets of the sex-specific FRU and DSX proteins and how they specify the function of these neurons. While sexual dimorphism in the number and connections of fru and dsx expressing neurons has been observed, a majority of the neurons that express the two regulators are present in both sexes. This poses the question which molecules define the sex-specific function of these neurons. Signaling molecules are likely to play a significant role. We have identified a predicted G-protein coupled receptor (GPCR), CG4395, that is required for male courtship behavior. The courtship defect in the mutants can be rescued by expression of the wildtype protein in fru neurons of adult males. The GPCR is expressed in a subset of fru-positive antennal glomeruli that have previously been shown to be essential for male courtship. Expression of 4395-RNAi in GH146 projection neurons lowers courtship. This suggests that signaling through the CG4395 GPCR in this subset of fru neurons is critical for male courtship behavior.     

Cell-Cell Recognition in the Regenerating Neuromuscular System of the Cockroach

SYNOPSIS. The neuromuscular system of the cockroach containsmotor neurons and muscles that can be identified in all individualinsects When the axons of these motor neurons are damaged theyregenerate and eventually reform synapses only with the originaltarget muscles However at early times after axotomy transientinappropriate functional connections are made between regeneratingneurons and muscles that theynever normally innervate Laterthe inappropriate synapses are inactivated, the inappropriateaxon branches eliminated and the original innervation patternreformed A cellcell recognition between identified motor neuronsand muscles is required to explain these observations, particularlyin light of experiments demonstrating the absence of competitionbetween appropriate and inappropriate axon terminals withinthe muscle. A minimum biochemical requirement of such a cell-cell recognitionis the existence of molecules whose presence in muscles correlateswith the innervation by identified motor neurons Using fluoresceinlabelled plant lectins to detect muscle surface glycoproteinssuch molecules have been identified In addition, there shouldbe molecular differences among the surfaces of the axon terminalsof the various identified motor neurons Hybrid oma techniqueshave enabled us to obtain monoclonal antibodies that bind tosurfaces of axon terminals of some motor neurons and not othersThese lectin receptors and antigens are good candidate recognitionmacromolecules Other molecules essential for axonal regenerationhave been identified by their presence in embryonic and adultregenerating neurons and their absence from intact adult neurons.     

Axon guidance in the inner ear

Statoacoustic ganglion (SAG) neurons send their peripheral processes to navigate into the inner ear sensory organs where they will ultimately become post-synaptic to mature hair cells. During early ear development, neuroblasts delaminate from a restricted region of the ventral otocyst and migrate to form the SAG. The pathfinding mechanisms employed by the processes of SAG neurons as they search for their targets in the periphery are the topic of this review. Multiple lines of evidence exist to support the hypothesis that a combination of cues are working to guide otic axons to their target sensory organs. Some pioneer neurites may retrace their neuronal migratory pathway back to the periphery, yet additional guidance mechanisms likely complement this process. The presence of chemoattractants in the ear is supported by in vitro data showing that the otic epithelium exerts both trophic and tropic effects on the statoacoustic ganglion. The innervation of ectopic hair cells, generated after gene misexpression experiments, is further evidence for chemoattractant involvement in the pathfinding of SAG axons. While the source(s) of chemoattractants in the ear remains unknown, candidate molecules, including neurotrophins, appear to attract otic axons during specific time points in their development. Data also suggest that classical axon repellents such as Semaphorins, Eph/ephrins and Slit/Robos may be involved in the pathfinding of otic axons. Morphogens have recently been implicated in guiding axonal trajectories in many other systems and therefore a role for these molecules in otic axon guidance must also be explored.     

Motor Axon Pathfinding

Motor neurons are functionally related, but represent a diverse collection of cells that show strict preferences for specific axon pathways during embryonic development. In this article, we describe the ligands and receptors that guide motor axons as they extend toward their peripheral muscle targets. Motor neurons share similar guidance molecules with many other neuronal types, thus one challenge in the field of axon guidance has been to understand how the vast complexity of brain connections can be established with a relatively small number of factors. In the context of motor guidance, we highlight some of the temporal and spatial mechanisms used to optimize the fidelity of pathfinding and increase the functional diversity of the signaling proteins.Motor neurons residing in the brain stem and spinal cord extend axons into the periphery and are the final relay cells for locomotor commands. These cells are among the longest projection neurons in the body and their axons follow stereotypical pathways during embryogenesis to synapse with muscle and sympathetic/parasympathetic targets. Cellular studies of motor axon navigation in developing chick and zebrafish embryos have shown that motor neurons located at different rostrocaudal positions show specific preferences for axonal pathways (see Landmesser 2001; Lewis and Eisen 2003 for reviews). This early cellular research laid the foundation for molecular studies of motor axon guidance by establishing the concept that motor neurons are in fact a diverse cell population. The molecular studies covered in this article have sought to identify genetic differences between motor neurons and to characterize the signaling pathways that underlie the specificity of motor axon targeting.     

Drosophila olfactory memory: single genes to complex neural circuits

A central goal of neuroscience is to understand how neural circuits encode memory and guide behaviour. Studying simple, genetically tractable organisms, such as Drosophila melanogaster, can illuminate principles of neural circuit organization and function. Early genetic dissection of D. melanogaster olfactory memory focused on individual genes and molecules. These molecular tags subsequently revealed key neural circuits for memory. Recent advances in genetic technology have allowed us to manipulate and observe activity in these circuits, and even individual neurons, in live animals. The studies have transformed D. melanogaster from a useful organism for gene discovery to an ideal model to understand neural circuit function in memory.     

Cell cycle and cell fate in the nervous system

Recently, a number of molecules originally thought to have a primary role in cell determination have been shown to affect the cell cycle at specific check points, while other molecules discovered for their roles in the cell cycle progression are known to affect the determination and differentiation of neurons. These discoveries have led to a more detailed investigation of the complex molecular machinery that co-ordinates proliferation and differentiation.     

Trying to understand axonal regeneration in the CNS of fish

In contrast to the situation in mammals and birds, neurons in the central nervous system (CNS) of fish—such as the retinal ganglion cells—are capable of regenerating their axons and restoring vision. Special properties of the glial cells and the neurons of the fish visual pathway appear to contribute to the success of axonal regeneration. The fish oligodendrocytes lack the axon growth inhibiting molecules that interfere with axonal extension in mammals. Instead, fish optic nerve oligodendrocytes support—at least in vitro—axonal elongation of fish as well as that of rat retinal axons. Moreover, the fish retinal ganglion cells re-express upon injury a set of growth associated cell surface molecules and equip the regenerating axons throughout their path and up into their target, the tectum opticum with these molecules. This may indicate that the injured fish ganglion cells reactivate the cellular machinery necessary for axonal regrowth and pathfinding. Furthermore, the target itself provides positional marker molecules even in adult fish. These marker molecules are required to guide the regenerating axons back to their retinotopic home territory within the tectum. © 1992 John Wiley & Sons, Inc.     

The G Protein regulators EGL-10 and EAT-16, the G<Subscript>i</Subscript>α GOA-1 and the G<Subscript>q</Subscript>α EGL-30 modulate the response of the <Emphasis Type="Italic">C. elegans</Emphasis>ASH polymodal nociceptive sensory neurons to repellents

Background  

Polymodal, nociceptive sensory neurons are key cellular elements of the way animals sense aversive and painful stimuli. In Caenorhabditis elegans, the polymodal nociceptive ASH sensory neurons detect aversive stimuli and release glutamate to generate avoidance responses. They are thus useful models for the nociceptive neurons of mammals. While several molecules affecting signal generation and transduction in ASH have been identified, less is known about transmission of the signal from ASH to downstream neurons and about the molecules involved in its modulation.     

BMPs as mediators of roof plate repulsion of commissural neurons

During spinal cord development, commissural (C) neurons, located near the dorsal midline, send axons ventrally and across the floor plate (FP). The trajectory of these axons toward the FP is guided in part by netrins. The mechanisms that guide the early phase of C axon extension, however, have not been resolved. We show that the roof plate (RP) expresses a diffusible activity that repels C axons and orients their growth within the dorsal spinal cord. Bone morphogenetic proteins (BMPs) appear to act as RP-derived chemorepellents that guide the early trajectory of the axons of C neurons in the developing spinal cord: BMP7 mimics the RP repellent activity for C axons in vitro, can act directly to collapse C growth cones, and appears to serve an essential function in RP repulsion of C axons.     

Advances in defining signaling networks for the establishment of neuronal polarity

Neurons are highly polarized cells that have structurally and functionally distinct processes called axons and dendrites. How neurons establish polarity is one of the fundamental questions of neuroscience. In the last decade, significant progress has been made in identifying and understanding the molecular mechanisms responsible for neuronal polarization, primarily through researches conducted on cultured neurons. Advances in phosphoproteomics technologies and molecular tools have enabled comprehensive signal analysis and visualization and manipulation of signaling molecules for analyzing neuronal polarity. Furthermore, advances in gene transfer techniques have revealed the role of extracellular and intracellular signaling molecules in neuronal polarization in vivo. This review discusses the latest insights and techniques for the elucidation of the molecular mechanisms that control neuronal polarity.