Receptor binding, internalization, and retrograde transport of neurotrophic factors

This review deals with the receptor interactions of neurotrophic factors, focusing on the neurotrophins of the nerve growth factor (NGF) family, the glial cell derived neurotrophic factor (GDNF) family, and the ciliary neurotrophic factor (CNTF) family. The finding that two proteins, p75^NTR and Trk, act as receptors for NGF in neurons generated the discovery of other neurotrophic factors/receptor families and has enhanced our understanding of the development, survival, regeneration, and degeneration of the nervous system. The kinetics of binding, the structure of the ligand-receptor complex, and the mechanism of retrograde transport of the neurotrophins are discussed in detail and compared to information available on the GDNF and CNTF families. Each neurotrophic factor family, i.e., NGF, GDNF, and CNTF, has a set of receptors with specificity for individual members of the family and a common receptor without member specificity that, in some families, generates the cellular signal and retrograde transport.     

Sensing life: regulation of sensory neuron survival by neurotrophins

Neurotrophins are a family of structurally and functionally related neurotrophic factors which, in mammals, include: nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and NT-4/5. In addition to their canonical role in promoting neuronal survival, these molecules appear to regulate multiple aspects of the development of the nervous system in vertebrates, including neuronal differentiation, axon elongation and target innervation, among others. Actions of neurotrophins and of their receptors in vivo are being analyzed by loss-of-function or gain-of-function experiments in mice. Here, we review the phenotypes of the primary sensory system in these mutant mouse strains and the different strategies specifically involved in the regulation of neuronal survival by neurotrophins in this portion of the nervous system. Received 10 December 2001; received after revision 11 May 2002; accepted 13 May 2002 RID="*" ID="*"Corresponding author.     

Neurotrophin signalling pathways regulating neuronal apoptosis

Recent evidence indicates that naturally occurring neuronal death in mammals is regulated by the interplay between receptor-mediated prosurvival and proapoptotic signals. The neurotrophins, a family of growth factors best known for their positive effects on neuronal biology, have now been shown to mediate both positive and negative survival signals, by signalling through the Trk and p75 neurotrophin receptors, respectively. The mechanisms whereby these two neurotrophin receptors interact to determine neuronal survival have been difficult to decipher, largely because both can signal independently or coincidentally, depending upon the cell or developmental context. Nonetheless, the past several years have seen significant advances in our understanding of this receptor signalling system. In this review, we focus on the proapoptotic actions of the p75 neurotrophin receptor (p75NTR), and on the interplay between Trk and p75NTR that determines neuronal survival.     

Expression of nerve growth factor-like polypeptides and immunoreactivity related to the two types of neurotrophin receptors in earthworm tissues

Nerve growth factor (NGF) belongs by sequence homology to the neurotrophins, a family of proteins binding the same p75 receptor and closely related members of the Trk family of receptor tyrosine kinases. Fundamental in the vertebrate nervous system, neurotrophin signals have also been suggested as essential for relatively complex nervous systems occurring in invertebrate species that live longer than Caenorhabditis elegans and Drosophila melanogaster. Mammalian neurotrophins have been found to influence invertebrate neuronal growth. However, there are only a few data on the presence of molecules related to neurotrophin signalling components in invertebrates. Our studies provide evidence that analogues of neurotrophins and neurotrophin receptors are expressed in Eisenia foetida earthworms. In particular, NGF-like and Trk-like immunoreactive proteins are both expressed in the nervous system, whereas p75-like positivity identifies tubular structures associated with dorsal pores that are involved in the earthworm response to mechanical irritation or stress. Received 12 November 2001; received after revision 8 January 2002; accepted 8 January 2002     

Nerve growth factor: structure and function

Neurotrophins are critical for the development and maintenance of the peripheral and central nervous system. These highly homologous, homodimeric growth factors control cell survival, differentiation, growth cessation, and apoptosis of sensory neurons. The biological functions of the neurotrophins are mediated through two classes of cell surface receptors, the Trk receptors and the p75 neurotrophin receptor (p75NTR). Nerve growth factor (NGF), the best characterized member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce cell death by binding to p75NTR. Recent domain deletion and mutagenesis studies have identified the membrane-proximal domain of the Trks as necessary and sufficient for ligand binding. Crystal structures of this domain of TrkA, TrkB, and TrkC, and an alanine scanning analysis of this domain of TrkA and TrkC have allowed identification of the ligand-binding site. The recent crystal structure of the complex between NGF and the ligand-binding domain of TrkA defines the orientation of NGF in the signaling complex, and eludicates the structural basis for binding and specificity in the family. Further structural work on NGF-TrkA-p7SNTR complexes will be necessary to address the many remaining questions in this complex signaling system.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Is there a space–time continuum in olfaction?

The coding of olfactory stimuli across a wide range of organisms may rely on fundamentally similar mechanisms in which a complement of specific odorant receptors on olfactory sensory neurons respond differentially to airborne chemicals to initiate the process by which specific odors are perceived. The question that we address in this review is the role of specific neurons in mediating this sensory system—an identity code—relative to the role that temporally specific responses across many neurons play in producing an olfactory perception—a temporal code. While information coded in specific neurons may be converted into a temporal code, it is also possible that temporal codes exist in the absence of response specificity for any particular neuron or subset of neurons. We review the data supporting these ideas, and we discuss the research perspectives that could help to reveal the mechanisms by which odorants become perceptions.     

Molecular and Cellular Basis of Regeneration and Tissue Repair

Although early after birth the central nervous system is more plastic than in the adult, it already displays limited regenerative capability. This becomes severely impaired at specific stages of embryonic development; however, the precise cellular and molecular basis of this loss is not fully understood. The chick embryo provides an ideal model for direct comparisons of regenerating and non-regenerating spinal cord within the same species because of its accessibility in ovo, the extensive knowledge of chick neural development and the molecular tools now available. Regenerative ability in the chick is lost at around E13, a relatively advanced stage of spinal cord development. This is most likely due to a complex series of events: there is evidence to suggest that developmentally regulated changes in the early response to injury, expression of inhibitory molecules and neurogenesis may contribute to loss of regenerative capacity in the chick spinal cord.     

Optical monitoring of activity of many neurons in invertebrate ganglia during behaviors

Summary Optical methods for monitoring neuron activity were developed because these methods lend themselves to simultaneous multiple-site measurements. With the use of new voltage-sensitive dyes, the dye-related pharmacology and photodynamic damage appear to be relatively unimportant. Using multiple-site measurements made with a 124-element photodiode array, we estimated that approximately 30 of the 200 neurons present in theNavanax buccal ganglion make action potentials during feeding and that approximately 300 of the 1100 neurons present in theNavanax buccal ganglion make are active during the gill-withdrawal reflex. The fact that a light mechanical touch to the siphon skin activated such a large number of neurons in the abdominal ganglion suggests that understanding the neuronal basis of the gill-withdrawal reflex and its behavioral plasticity may be forbiddingly difficult.     

Neural map formation in the mouse olfactory system

In the mouse olfactory system, odorants are detected by ~1,000 different odorant receptors (ORs) produced by olfactory sensory neurons (OSNs). Each OSN expresses only one functional OR species, which is referred to as the “one neuron–one receptor” rule. Furthermore, OSN axons bearing the same OR converge to a specific projection site in the olfactory bulb (OB) forming a glomerular structure, i.e., the “one glomerulus–one receptor” rule. Based on these basic rules, binding signals of odorants detected by OSNs are converted to topographic information of activated glomeruli in the OB. During development, the glomerular map is formed by the combination of two genetically programmed processes: one is OR-independent projection along the dorsal–ventral axis, and the other is OR-dependent projection along the anterior-posterior axis. The map is further refined in an activity-dependent manner during the neonatal period. Here, we summarize recent progress of neural map formation in the mouse olfactory system.     

Signaling in the Chemosensory Systems

The small nematode Caenorhabditis elegans lives in the soil, where mechanical, thermal and most of all chemical stimuli strongly influence its behavior. Here we briefly review how chemical sensitivity is organized at the cellular and molecular level in this organism. C. elegans has less than 40 chemosensory neurons. With few exceptions each neuron senses more than one substance and each substance is sensed by more than one neuron. At the molecular level, as in other organisms, also in C. elegans, seven transmembrane G-protein-coupled receptors (GPCRs), heterotrimeric G proteins, cyclic nucleotidegated ion channels, TRP channels and Ca++ play crucial roles in chemical sensitivity. An unusual feature, possibly due to C. elegans's strong dependence on chemical cues, is the very large number of GPCR chemoreceptor genes (1300-1700) coded in its genome. Genetic approaches have also allowed the identification of new molecules involved in chemical sensitivity that would not have been discovered otherwise. In addition to the basic factors involved in primary signalling, the studies in C. elegans have revealed a network of regulatory pathways and molecules suggesting that fine modulation of the responsiveness of neurons is important, possibly to allow worms to negotiate a continuously changing environment. The experimental versatility of C. elegans has made it possible, in many cases, to determine precisely in which neuron a given molecule or pathway is required and for which biological response. This type of information can contribute to the general field of sensory signalling because it provides correlations between the biochemical properties of molecules and their cellular functions and between these and the in vivo behavioral responses of the animal.     

Substance P-like immunoreactivity in the frog dorsal root ganglia

Summary The distribution of substance P-like immunoreactivity was studied in the thoracic dorsal root ganglia of the frogRana esculenta by immunohistochemistry. Substance P-like immunoreactivity was contained in approximately 50% of primary sensory neurons. The immunoreactive fibers arising from the cell bodies are collected in small bundles within the ganglia neuropil before entering the central and peripheral roots.     

Analysis of synaptic integration using the laser photoinactivation technique

Summary Crickets (and many other insects) have two antenna-like appendages at the rear of their abdomen, each of which is covered with hundreds of filiform hairs resembling the bristles on a bottle brush. Deflection of these filiform hairs by wind currents activates mechanosensory neurons at the base of the hairs. The axons from these sensory neurons project into the terminal abdominal ganglion to form a topographic representation (or map) containing information about the direction, velocity and acceleration of wind currents around the animal. Information is extracted from this map by primary sensory interneurons that are also located within the terminal abdominal ganglion. In this paper, we review the progress that has been made toward understanding the mechanisms underlying directional sensitivity of an identified sensory interneuron in the cricket,Acheta domesticus. The response properties of the cell have been found to depend to a large extent upon the structure of its dendritic branches, which determines its synaptic connectivity with the sensory afferents in the map of wind space and the relative efficacy of its different synaptic inputs.     

Retinoic acid signaling and neurogenic niche regulation in the developing peripheral nervous system of the cephalochordate amphioxus

The retinoic acid (RA) signaling pathway regulates axial patterning and neurogenesis in the developing central nervous system (CNS) of chordates, but little is known about its roles during peripheral nervous system (PNS) formation and about how these roles might have evolved. This study assesses the requirement of RA signaling for establishing a functional PNS in the cephalochordate amphioxus, the best available stand-in for the ancestral chordate condition. Pharmacological manipulation of RA signaling levels during embryogenesis reduces the ability of amphioxus larvae to respond to sensory stimulation and alters the number and distribution of ectodermal sensory neurons (ESNs) in a stage- and context-dependent manner. Using gene expression assays combined with immunohistochemistry, we show that this is because RA signaling specifically acts on a small population of soxb1c-expressing ESN progenitors, which form a neurogenic niche in the trunk ectoderm, to modulate ESN production during elongation of the larval body. Our findings reveal an important role for RA signaling in regulating neurogenic niche activity in the larval amphioxus PNS. Although only few studies have addressed this issue so far, comparable RA signaling functions have been reported for neurogenic niches in the CNS and in certain neurogenic placode derivatives of vertebrates. Accordingly, the here-described mechanism is likely a conserved feature of chordate embryonic and adult neural development.     

The hypothalamus and the neurobiology of drug seeking

The hypothalamus is a neural structure critical for expression of motivated behaviours that ensure survival of the individual and the species. It is a heterogeneous structure, generally recognised to have four distinct regions in the rostrocaudal axis (preoptic, supraoptic, tuberal and mammillary). The tuberal hypothalamus in particular has been implicated in the neural control of appetitive motivation, including feeding and drug seeking. Here we review the role of the tuberal hypothalamus in appetitive motivation. First, we review evidence that different regions of the hypothalamus exert opposing control over feeding. We then review evidence that a similar bi-directional regulation characterises hypothalamic contributions to drug seeking and reward seeking. Lateral regions of the dorsal tuberal hypothalamus are important for promoting reinstatement of drug seeking, whereas medial regions of the dorsal tuberal hypothalamus are important for inhibiting this drug seeking after extinction training. Finally, we review evidence that these different roles for medial versus lateral dorsal tuberal hypothalamus in promoting or preventing reinstatement of drug seeking are mediated, at least in part, by different populations of hypothalamic neurons as well as the neural circuits in which they are located.     

Galanin – 25 years with a multitalented neuropeptide

Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics.     

二进神经网络表达奇偶校验问题的隐元最小数目上界

二进神经网络采用线性分类,是结构简单又易于实现的一类神经网络,在许多应用领域中都有重要研究价值.对于单隐层二进神经网络,目前隐层规模的确定问题仍然没有明确的研究结论.本文在研究隐层规模问题的过程中,提出了布尔空间的最多孤立样本问题.在二进神经网络隐层神经元各自表达一个"与"关系,所有隐层神经元通过输出元形成"或"关系的情况下,证明了实现最多孤立样本问题需2n?1个隐层神经元.更重要的是,指出了n元奇偶校验问题和最多孤立样本结构的等价性.进一步地,通过引入隐层抑制神经元将隐元数目降为n,说明了抑制神经元在二进神经网络中的重要作用.最后,在Hamming球与SP函数的基础上,揭示出抑制神经元和n元奇偶校验问题的逻辑关系,并给出了奇偶校验问题的逻辑式表达.     

The Ror receptor tyrosine kinase family

Receptor tyrosine kinases (RTKs) participate in numerous developmental decisions. Ror RTKs are a family of orphan receptors that are related to muscle specific kinase (MuSK) and Trk neurotrophin receptors. MuSK assembles acetylcholine receptors at the neuromuscular junction [1, 2], and Trk receptors function in the developing nervous system (reviewed in [3-5]). Rors have been identified in nematodes, insects and mammals. Recent studies have begun to shed light on Ror function during development. In most species, Rors are expressed in many tissue types during development. Analyses of mutants that are defective in the single nematode Ror demonstrate a role in cell migration and in orienting cell polarity. Mice lacking one of the two Ror gene products display defects in bone and heart formation. Similarly, two different human bone development disorders, dominant brachydactyly B and recessive Robinow syndrome, result from mutations in one of the human Ror genes. Received 17 April 2001; received after revision 2 July 2001; accepted 4 July 2001