Fibroblast growth factors as regulators of central nervous system development and function

Fibroblast growth factors (FGFs) are multifunctional signaling proteins that regulate developmental processes and adult physiology. Over the last few years, important progress has been made in understanding the function of FGFs in the embryonic and adult central nervous system. In this review, I will first discuss studies showing that FGF signaling is already required during formation of the neural plate. Next, I will describe how FGF signaling centers control growth and patterning of specific brain structures. Finally, I will focus on the function of FGF signaling in the adult brain and in regulating maintenance and repair of damaged neural tissues.     

Glycoproteins associated with myelin in the central nervous system

Purified myelin fractions from the central nervous system contain one major myelin-associated glycoprotein and approximately 16 minor glycoproteins. While the genuine association of the major myelin-associated glycoprotein with the oligodendroglial myelin unit is demonstrated, the possibility exists that several of the minor glycoproteins have their origin in contaminating membranes not related to myelin. The major myelin-associated glycoprotein is probably not present in compacted myelin, but immunocytochemical and subfractionation studies indicate that it is confined to the periaxonal and paranodal region of the myelin sheath. In experimental demyelination and multiple sclerosis, the major glycoprotein is the first myelin constituent to be affected. Its localization on the membrane surface where myelin and axolemma are in close contact, and other indirect evidence indicate that the major glycoprotein, and possibly other myelin-associated glycoproteins, could play a role in the process of myelination and myelin maintenance.     

Smad1 and Smad8 function similarly in mammalian central nervous system development

Smads 1, 5, and 8 are the intracellular mediators for the bone morphogenetic proteins (BMPs), which play crucial roles during mammalian development. Previous research has shown that Smad1 is important in the formation of the allantois, while Smad5 has been shown to be critical in the process of angiogenesis. To further analyze the BMP-responsive Smads, we disrupted the murine Smad8 gene utilizing the Cre/loxP system. A Smad8 hypomorphic allele (Smad8(Deltaexon3)) was constructed that contains an in-frame deletion of exon 3, removing one-third of the MH2 domain and a small portion of the linker region. Xenopus injection assays indicated that this Smad8 deletion allele is still functional but has reduced ventralizing capability compared to the wild type. Although Smad8(Deltaexon3/Deltaexon3) embryos are phenotypically normal, homozygotes of another hypomorphic allele of Smad8 (Smad8(3loxP)) containing a neomycin cassette within intron 3, phenocopy an embryonic brain defect observed in roughly 22% of Smad1(+/)(-) embryos analyzed at embryonic day 11.5. These observations suggest that BMP-responsive Smads have critical functions in the development of the mammalian central nervous system.     

The role of astrocyte-secreted matricellular proteins in central nervous system development and function

Matricellular proteins, such as thrombospondins (TSPs1-4), SPARC, SPARC-like1 (hevin) and tenascin C are expressed by astrocytes in the central nervous system (CNS) of rodents. The spatial and temporal expression patterns of these proteins suggest that they may be involved in important developmental processes such as cell proliferation and maturation, cell migration, axonal guidance and synapse formation. In addition, upon injury to the nervous system the expression of these proteins is upregulated, suggesting that they play a role in tissue remodeling and repair in the adult CNS. The genes encoding these proteins have been disrupted in mice. Interestingly, none of these proteins are required for survival, and furthermore, there are no evident abnormalities at the gross anatomical level in the CNS. However, detailed analyses of some of these mice in the recent years have revealed interesting CNS phenotypes. Here we will review the expression of these proteins in the CNS. We will discuss a newly described function for thrombospondins in synapse formation in the CNS in detail, and speculate whether other matricellular proteins could play similar roles in nervous system development and function.     

Dual function of polysialic acid during zebrafish central nervous system development.

Polysialic acid (PSA), a carbohydrate epitope attached to the neural cell adhesion molecule, serves as a modulator of axonal interactions during vertebrate nervous system development. We have used PSA-specific antibodies and whole-mount immunocytochemistry to describe the spatiotemporal expression pattern of PSA during zebrafish central nervous system development. PSA is transiently expressed on all cell bodies and, except for the posterior commissure, it is not found on axons. Floorplate cells in the spinal cord and hindbrain strongly express PSA throughout development. Enzymatic removal of PSA leads to a defasciculated growth pattern of the posterior commissure and also affects distinct subsets of commissural axons in the hindbrain, which fail to cross the midline. Whereas the disordered growth pattern of hindbrain commissures produced by PSA-removal could be mimicked by injections of soluble PSA, the growth of axons in the posterior commissure was unaffected by such treatment. These results suggest that there are distinct mechanisms for PSA action during axon growth and pathfinding in the developing zebrafish CNS.     

NMDA受体与中枢神经系统的发育

离子型谷氨酸受体分为NMDA型和非NMDA型两类,其中NMDA型受体与中枢神经系统发育关系密切。本文综述了NMDA受体的分子特性及NMDA受体五种亚单位NR1、NR2A、NR2B、NR2C和NR2D在动物出生后脑内的时空表达;NMDA受体亚单位在发育中的作用以及NMDA受体活性的胞内调节机制。     

Evolution of a neuroprotective function of central nervous system myelin

The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when a tetraspan membrane protein, myelin proteolipid protein (PLP), replaced the type I integral membrane protein, P0, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P0 instead of PLP in CNS myelin. In the absence of PLP, the ancestral P0 provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P0 is the major structural protein today. The PLP-P0 shift resulted in reduced myelin internode length, degeneration of myelinated axons, severe neurological disability, and a 50% reduction in lifespan. Mice with equal amounts of P0 and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia.     

Insulin-like growth factor-I and central nervous system development.

Insulin-like growth factor-I (IGF-I), a 70-amino acid-protein structurally similar to insulin, promotes cell proliferation and differentiation in multiple tissues. Most of its effects are mediated by the Type I IGF receptor (IGF-IR), a heterotetramer that has tyrosine kinase activity and phosphorylates insulin receptor substrates (IRS-1 and 2) which leads to the activation of two downstream signaling cascades: the MAP kinase and the phosphatidylinositol 3-kinase (P3K) cascades. The growth-promoting effects of IGF-I are prominent in the nervous system, qualifying this molecule as a neurotrophin. Although the primary regulator of IGF-I expression is growth hormone (GH), the developmental expression of IGF-I in various tissues precedes that of GH, supporting an independent role of IGF-I in embryonic and fetal life [1]. This review will examine the effect of IGF-I on central nervous system (CNS) development. The specialized structure of the CNS is the product of a complex series of biological events which result from the interaction between the cells' genetic program and environmental influences. CNS development begins in the embryo with dorsal ectodermal cell proliferation to form the neural plate, and, with its closure, the neural tube, followed by the rapid division of pluripotential cells, their migration to the periphery of the neural tube, and differentiation into neural or glial cells. During the latter stages, cells form special structures such as nuclei, ganglia, cerebral cortical layers, and they also develop a network with their cytoplasmic extensions, neurites. Many more cells and connections are generated in fetal life than are found in the mature organism. This excessive production of some cell groups and neurites may compensate for tissue loss due to various injuries, and their selective elimination also constitutes an efficient way to organize the architecture of the CNS. This elimination is believed to be accomplished by apoptosis. The cells' intrinsic program for development includes the expression of various genes at different times. Environmental influences, such as extracellular matrix (ECM) molecules that attract or repel cells, afferent inputs, and target-derived diffusible molecules modify and modulate cellular behavior. IGF-I is among the molecules which affect several steps involved in development.     

On the interaction between the central nervous system and the peripheral motor system

The problem of the control of voluntary human movements is considered from a cybernetic point of view. The human motor system is considered to be divided into a central part and a peripheral part. The peripheral part is relatively well known and may be regarded as a set of subsystems with well known input-output relations. The interaction between the peripheral part and the central part is related to the mechanisms of the peripheral motor part. With regard to the central part two different types of control mechanisms are possible, a) an intricate functioning of the central part which generates the control signals with regard to internal and external dynamical factors, b) the central part has some degree of independence with respect to the dynamics of the peripheral mortor part. In the latter case the central part prescribes the desired movement exactly, but the final performance of the movement is also brought about by peripheral feedback mechanisms. As a functional form of the interaction between the central part and the peripheral part it might be that the control signals are encoded in a way that is related to the muscle lengths.     

NMDA受体与中枢神经系统发育

中枢神经系统兴奋性氨基酸离子型受体－ＮＭＤＡ受体,是由ＮＭＤＡＲ１和ＮＭＤＡＲ２两个亚单位共同构成的受体通道复合体。ＮＭＤＡ受本激活后可引起神经元细胞对Ｎａ＾＋,Ｋ＾＋和Ｃａ＾２＋通透性增强,产生兴奋性突触后电位,在中枢神经发育的过程中,ＮＭＤＡ受体通过不同亚型的选择性表达,改变自身的结构和功能,进而影响ＮＭＤＡ受体介导的Ｃａ＾２＋内流,调节神经元内Ｃａ＾２＋依赖的第二信使系统,最终实现对中枢神经     

Differential expression and function of the Drosophila Pax6 genes eyeless and twin of eyeless in embryonic central nervous system development

We analyzed the expression and function of eyeless (ey) and twin of eyeless (toy) in the embryonic central nervous system (CNS) of Drosophila. Both genes are differentially expressed in specific neuronal subsets (but not in glia) in every CNS neuromere, and in the brain, specific cell populations co-expressing both proteins define a longitudinal domain which is intercalated between broad exclusive expression domains of ey and toy. Studies of genetic null alleles and dsRNA interference did not reveal any gross neuroanatomical effects of ey, toy, or ey/toy elimination in the embryonic CNS. In contrast, targeted misexpression of ey, but not of toy, resulted in profound axonal abnormalities in the embryonic ventral nerve cord and brain.     

The development of isolated central nervous system preparations

1. Use of invertebrate isolated CNS preparations showed that identified neurons have distinct specific repeatable pharmacological properties. 2. Isolated CNS preparations have been developed from invertebrates to include fish, amphibian, reptile and mammal CNS preparations. 3. The isolated mammalian (mouse, hamster, rat, guinea pig) CNS preparation can remain alive for up to 72 hr and show cells with good resting potentials, action potentials; good functional pathways and tracts; and good responses to drug application. 4. Some possible future developments of isolated mammalian CNS preparations are described.     

Regulation of proliferation during central nervous system development

The retina is one of the best-characterized regions of the central nervous system (CNS) and has served as a model for many of the principles that now form the foundation for CNS development. In the past several years, a number of advances have been made in our understanding of the coordination of proliferation and cell fate specification during retinal development. In this review, we will draw on findings from studies of the retina and highlight similarities and differences in other regions in the CNS, namely the cerebellum and cortex. We will present a framework in which to pose challenges and outstanding questions for future studies on the coordination of proliferation and cell fate specification in the developing CNS.     

Organization and function of a central nervous system circadian oscillator: the suprachiasmatic hypothalamic nucleus

Circadian rhythms in mammals are generated by endogenous neural oscillating systems entrained to the light-dark cycle by specific visual pathways. We conclude from available data that the suprachiasmatic hypothalamic nuclei (SCN) are the principal circadian oscillators in the rodent brain and that a retinohypothalamic projection terminating in the SCN is the primary visual pathway subserving entrainment of circadian rhythms. Recent anatomical studies demonstrate that the SCN have distinct subdivisions in the rat. A dorsomedial component is comprised of a distinct neuronal population and contains a large population of interneurons, many of which produce peptides. It receives no direct or indirect visual input and has only very limited projections outside the SCN. A ventrolateral component is also made up of a distinctive neuronal population, receives both direct and indirect visual projections, and provides the major external projections of the SCN, which are to the hypothalamus, particularly the hypophysiotrophic area. The SCN are viewed in this review as containing multiple, mutually coupled oscillating systems that arise from a developmental process of interconnecting individual neuronal circadian oscillators into circuits that form the oscillating systems. A model for the organization of the systems is presented.     

Mitochondrial calcium function and dysfunction in the central nervous system

The ability of isolated brain mitochondria to accumulate, store and release calcium has been extensively characterized. Extrapolation to the intact neuron led to predictions that the in situ mitochondria would reversibly accumulate Ca²⁺ when the concentration of the cation in the vicinity of the mitochondria rose above the ‘set-point’ at which uptake and efflux were in balance, storing Ca²⁺ as a complex with phosphate, and slowly releasing the cation when plasma membrane ion pumps lowered the cytoplasmic free Ca²⁺. Excessive accumulation of the cation was predicted to lead to activation of the permeability transition, with catastrophic consequences for the neuron. Each of these predictions has been confirmed with intact neurons, and there is convincing evidence for the permeability transition in cellular Ca²⁺ overload associated with glutamate excitotoxicity and stroke, while the neurodegenerative disease in which possible defects in mitochondrial Ca²⁺ handling have been most intensively investigated is Huntington's Disease. In this brief review evidence that mitochondrial Ca²⁺ transport is relevant to neuronal survival in these conditions will be discussed.