Progesterone as a neurosteroid: Actions within the nervous system

Summary 1. Some progesterone is synthesized within both the central and the peripheral nervous systems, where it regulates neurotransmission and important glial functions, such as the formation of myelin. Progesterone can thus be designated a neurosteroid.2. Steroids act not only on the brain, but also on peripheral nerves, which offer many advantages to study the biological significance of locally produced neurosteroids: their remarkable plasticity and regenerative capacity and their relatively simple structure.3. By using the regenerating mouse sciatic nerve as a model, we have shown that progesterone synthesized by rat Schwann cells promotes the formation of new myelin sheaths. Progesterone also increases the number of myelinated axons when added at a low concentration to cocultures of Schwann cells and sensory neurons.4. These findings show a function on myelination for locally produced progesterone and suggest a new pharmacological approach of myelin repair.     

Amphibian sympathetic ganglia as a model system for investigating regeneration in the vertebrate peripheral nervous system

1. The paravertebral sympathetic ganglion of the bullfrog serves as an excellent experimental system in which to study the response of vertebrate neurones to axotomy and the mechanisms associated with regeneration. 2. Various types of lesions to the axons (axotomy) of these neurones promote distinct and reproducible changes in the electrophysiological properties of the cell bodies which are not a consequence of changes in cell body morphology. 3. The axotomy-induced increase in spike width and decrease in the amplitude of the action potential after-hyperpolarization may allow an increase in Ca2+ influx and thereby promote regrowth. 4. The axotomy-induced decrease in after-hyperpolarization duration may reflect the disconnection of the neurone with its target and the loss of available nerve growth factor (NGF) from the target. 5. Experiments with NGF antibodies provide evidence that an NGF-like substances serves to maintain the normal electrophysiological characteristics of amphibian sympathetic neurones.     

Glycine-receptors in the vertebrate central nervous system

Evidence for the existence of glycine-receptors in the vertebrate central nervous system (CNS) has been reviewed and analyzed. Biochemical studies have supported iontophoretic findings that such receptors exist in several regions of the CNS. Subcellular studies on the displacement of 3H-strychnine binding by glycine and on the effects of strychnine on 3H-glycine binding have revealed that strychnine does not interact directly with glycine-receptors, lending support to studies performed in situ. Approaches toward glycine-receptors remain limited due to the inavailability of a specific glycine-antagonist.     

The collagen of the vertebrate peripheral nervous system

Summary Nerves and ganglia from a variety of fish, amphibian, reptilian and mammalian species were studied by optical and electron microscopy. Observations using the Picrosirius-polarization method strongly suggest that two different types of collagen fibers are present in the connective tissues of nerves and ganglia. Electron microscopy of nerves and ganglia showed the presence of two different collagen fibril populations, distinguishable on the basis of diameter, located in different compartments of these structures. Thicker fibrils are present in nerve and ganglionic epineurium. Thinner fibrils are present in the endoneurium, surrounding nerve fibers and ganglionic cells, and between the concentric layers of perineurial cells. These results were consistently observed in all species studied and very probably represent a general phenomenon in vertebrates.This work was aided by a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo     

Axon guidance in the vertebrate central nervous system

The development of connections in the central nervous system depends on the ability of the tips of growing axons to find their appropriate, often distant, target field. Factors that regulate axon outgrowth may be distinct from those that influence direction finding. Tissue culture methods have helped to distinguish between possible in vivo mechanisms and, in some cases, have identified candidate molecules.     

Pattern formation in the vertebrate nervous system.

In recent years, the classical approaches of experimental embryology have been used in combination with more modern techniques to investigate aspects of neurogenesis. This combination has advanced our knowledge of several areas of neuronal development, including the lineages of neuronal precursors, the segmentation of the nervous system, and the patterning of the neural tube.     

Segmentation and the development of the vertebrate nervous system

1. Recent experiments on the development of neural segmentation in chick embryos are reviewed. 2. Segmentation of the spinal peripheral nerves is governed by a subdivision of the somite-derived sclerotome into anterior and posterior halves. Migrating neural crest cells and outgrowing motor axons are confined to the anterior sclerotome as a result, in part, of inhibitory interactions with posterior sclerotome cells. 3. The sclerotomal distribution of certain molecules known to influence growing nerve cells in vitro, namely laminin, fibronectin, N-CAM, N-Cadherin and J1/tenascin/cytotactin, suggest that these molecules play no critical role in determining the preference of nerve cells for anterior sclerotome. 4. Peanut agglutinin (PNA) recognises cell surface-associated components on posterior cells which, when incorporated into liposomes, cause the abrupt collapse of sensory growth cones in vitro. The PNA receptor(s) may be inhibitory for nerve cells in vivo. 5. The chick hindbrain epithelium is segmented early in its development. Each branchiomotor nucleus in the series of cranial nerves V, VII and IX derives from a pair of segments lying in register with an adjacent branchial arch. Neurogenesis of motor and reticular axons begins in alternate segments, suggesting parallels with insect pattern formation.     

Radial glia serve as neuronal progenitors in all regions of the central nervous system

Radial glial cells function during CNS development as neural progenitors, although their precise contribution to neurogenesis remains controversial. Recent work has argued that regional differences may exist regarding the neurogenic potential of radial glia. Here, we show that the vast majority of neurons in all brain regions derive from radial glia. Cre/loxP fate mapping and clonal analysis demonstrate that radial glia throughout the CNS serve as neuronal progenitors and that radial glia within different regions of the CNS pass through their neurogenic stage of development at distinct time points. Thus, radial glial populations within different CNS regions are not heterogeneous with regard to their potential to generate neurons versus glia.     

WNTs in the vertebrate nervous system: from patterning to neuronal connectivity

WNT signalling has a key role in early embryonic patterning through the regulation of cell fate decisions, tissue polarity and cell movements. In the nervous system, WNT signalling also regulates neuronal connectivity by controlling axon pathfinding, axon remodelling, dendrite morphogenesis and synapse formation. Studies, from invertebrates to mammals, have led to a considerable understanding of WNT signal transduction pathways. This knowledge provides a framework for the study of the mechanisms by which WNTs regulate diverse neuronal functions. Manipulation of the WNT pathways could provide new strategies for nerve regeneration and neuronal circuit modulation.     

A rectifying electrotonic synapse in the central nervous system of a vertebrate

The adductor muscles of the pectoral fins of the hatchetfish Gasteropelecus are innervated by bilateral pools of about 40 motoneurons which lie primarily in the first spinal segment. A pair of giant fibers on each side of the medulla send processes ventroposteriorly to the motoneuron pools. Electrophysiological evidence indicates that giant fibers are presynaptic to ipsilateral motoneurons, but not to contralateral ones. Transmission across the giant fiber, motoneuron synapse is electrically mediated as is indicated by direct measurement of electrotonic spread in either direction across the synapse, and by the extremely short latency of the giant fiber postsynaptic potentials (PSP's) in the motoneuron. The coupling resistance across the synapse was calculated from measurements of input and transfer resistance. The coupling resistance rectifies in such a way as to facilitate spread of depolarization from giant fiber to motoneuron, and to oppose transmission in the opposite direction. As a consequence of rectification, the giant fiber PSP in a motoneuron is augmented by hyperpolarization of the motoneuron. The coupling resistance calculated on the basis of this effect is in good agreement with calculations from input and transfer resistance data. Rectification at the electrotonic synapses may permit the motoneurons to act in small swimming movements as well as to fire synchronously in an extremely fast escape reflex mediated by Mauthner and giant fibers.     

Mechanisms of ventral patterning in the vertebrate nervous system

Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS.     

Chordate origins of the vertebrate central nervous system.

Fine structural, computerized three-dimensional (3D) mapping of cell connectivity in the amphioxus nervous system and comparative molecular genetic studies of amphioxus and tunicates have provided recent insights into the phylogenetic origin of the vertebrate nervous system. The results suggest that several of the genetic mechanisms for establishing and patterning the vertebrate nervous system already operated in the ancestral chordate and that the nerve cord of the proximate invertebrate ancestor of the vertebrates included a diencephalon, midbrain, hindbrain, and spinal cord. In contrast, the telencephalon, a midbrain-hindbrain boundary region with organizer properties, and the definitive neural crest appear to be vertebrate innovations.     

Plasticity and stem cells in the vertebrate nervous system

How and when do vertebrate neural precursor cells choose their fates? While some studies suggest a series of commitments on the road to fate choice, many recent experiments indicate that precursor fate choices can often be changed. Additionally, the identification of common gene control mechanisms in precursors suggest that these cells share fundamental properties throughout development.     

ATR maintains select progenitors during nervous system development

The ATR (ATM (ataxia telangiectasia mutated) and rad3-related) checkpoint kinase is considered critical for signalling DNA replication stress and its dysfunction can lead to the neurodevelopmental disorder, ATR-Seckel syndrome. To understand how ATR functions during neurogenesis, we conditionally deleted Atr broadly throughout the murine nervous system, or in a restricted manner in the dorsal telencephalon. Unexpectedly, in both scenarios, Atr loss impacted neurogenesis relatively late during neural development involving only certain progenitor populations. Whereas the Atr-deficient embryonic cerebellar external germinal layer underwent p53- (and p16(Ink4a/Arf))-independent proliferation arrest, other brain regions suffered apoptosis that was partially p53 dependent. In contrast to other organs, in the nervous system, p53 loss did not worsen the outcome of Atr inactivation. Coincident inactivation of Atm also did not affect the phenotype after Atr deletion, supporting non-overlapping physiological roles for these related DNA damage-response kinases in the brain. Rather than an essential general role in preventing replication stress, our data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis.     

Stabilizing the regionalisation of the developing vertebrate central nervous system

During embryonic development, a number of tissues are patterned by their subdivision into domains with distinct regional identity. An important question is how sharp interfaces are established and maintained between adjacent domains despite the potential for scrambling due to cell intermingling during tissue growth. Two mechanisms have been found to underlie the maintenance of sharp interfaces: the specific restriction of cell mixing across boundaries, or the switching of identity of cells that cross between domains. We review the evidence for these mechanisms at distinct boundaries in the developing vertebrate central nervous system, and discuss what is known about their molecular mediators.