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Control of directional axon growth is fundamental to correct wiring in the nervous system, and glia are thought to play an important role. New work in the zebrafish lateral line shows that glia are not required for axonal pathfinding but are required for normal mature nerve organization.
Mutations in the cell adhesion molecule L1 cause severe developmental anomalies in the human nervous system. Recent descriptions of L1 gene knock-out mice from three research groups demonstrate that these mice are strikingly similar to humans with mutations in the L1 gene. In both humans and mice there are defects in the development of the corticospinal tract and cerebellar vermis, hydrocephalus, and impaired learning. The production of a viable animal model for X-linked hydrocephalus suggests that unanswerable questions posed by the human disease will finally be approachable using modern experimental methods.
The erbB4 gene encodes one of the four members of the mammalian ErbB family of transmembrane tyrosine kinases. The ErbB4 protein plays a role as a receptor for the neuregulins, a large group of structurally related molecules and a few other epidermal growth factor (EGF)-related polypeptides, such as heparin-binding EGF, betacellulin and epiregulin. The importance of this receptor tyrosine kinase in development has been demonstrated by the generation of mice with a targeted inactivation of the erbB4 gene. Such mice die by embryonic day eleven due to defective trabeculation in the heart, precluding analysis of phenotypes at later stages in development and in the adult. Now, using two unique genetic approaches our laboratories succeeded in overcoming this obstacle. In the first approach, the heart defects of ErbB4 null mutant mice were rescued by transgenic expression of an ErbB4 cDNA under a cardiac-specific myosin promoter. This allowed the generation of ErbB4 mutants that develop into adulthood and are fertile. In the second approach, the role of ErbB4 during mammary gland development was specifically addressed by Cre-mediated deletion of both erbB4 alleles within the mammary epithelium. Below we discuss the progress made studying these genetic models in understanding the physiological roles of ErbB4 with a focus on the mammary gland and the nervous system.
The Drosophila Delta gene and its vertebrate homologues are ligands for the Notch receptor and are involved in a variety of developmental processes, including neurogenesis, boundary formation, and axon guidance. This study deals with the ectodermal expression and function of X-Delta-2 during early Xenopus laevis development. X-Delta-2 is expressed, from early neurula stages on, throughout the central nervous system (CNS; forebrain, eyes, midbrain, hindbrain, and spinal cord) and in the majority of the cranial placodes. Loss of function experiments using a morpholino knockdown approach revealed that X-Delta-2 is necessary for hindbrain segmentation and the correct specification of the anterior CNS. X-Delta-2 also seems to be important in the determination of the size of the eyes. Furthermore, our results suggest that X-Delta-2 is involved in the migration of the cranial placodes cells, as well the migration of the cranial neural crest cells.
The Eph family represents the largest subfamily of receptor tyrosine kinases. Its members are predominantly expressed in the developing and adult nervous system. Besides playing an important role in the contact-mediated repulsion of axons, they have recently also been implicated in the control of cell migration. Characteristics of the Eph family are extended promiscuity in the interaction between receptors and ligands, the necessity of membrane attachment of the ligands to exert their function, the lack of induction of mitogenic responses, and the bi-directional signalling of receptors and ligands.
Endogenous nitric oxide (NO) has recently been shown to affect cell cycle progression in the neural tube (NT) of the chick embryo. High NO levels trigger entry into S phase basally, while low NO levels facilitate mitosis apically. Here, we further explore the involvement of NO in determining cell numbers in the chick NT. In addition to the effect of short-term (6 h) NOS inhibition, we have observed a concomitant decrease in programmed cell death (PCD). Paradoxically, long-term (12 h) NOS inhibition caused an increase in PCD to compensate for the high proliferation rate under these conditions. Long-term treatment with a NO donor caused a decrease in S phase and increased PCD. The effects produced by the NO donor could be alleviated by folic acid that facilitated entry into S phase and prevented PCD. The effects produced by NOS inhibition (12 h) could be overcome by an embryo extract, used as a source of extracellular survival factors that enhanced proliferation and prevented PCD. Taken together, these data demonstrate that changing endogenous NO levels affect the balance between cell proliferation and PCD in NT of the developing chick embryo.
We have isolated a novel member of the tyrosine protein kinase family of cell surface receptors. This gene, designated trkB, is highly related to the human trk proto-oncogene. At the amino acid level, their respective products share a 57% homology in their extracellular regions including 9 of the 11 cysteines present in the trk proto-oncogene. This homology increases to 88% within their respective tyrosine kinase catalytic domains. Both trk and trkB are equally distantly related to the other members of this gene family of receptors. A biologically active cDNA clone of trkB can direct the synthesis of gp145trkB, a glycoprotein of 145 kd of which only 93 kd correspond to its polypeptide backbone. In adult mice, trkB is preferentially expressed in brain tissue, although significant levels of trkB RNA have also been observed in lung, muscle and ovaries. In addition, trkB transcripts can be detected in mid and late gestation embryos. The trkB locus exhibits a complex pattern of transcription. At least seven RNA species ranging in size from approximately 9 kb to 2 kb have been identified in brain. However, only a subset of these transcripts appears to be expressed in the other tissues. In situ hybridization analysis of 14 and 18 day old mouse embryos indicates that trkB transcripts are localized in the central (CNS) and peripheral (PNS) nervous systems, including brain, spinal cord, spinal and cranial ganglia, paravertebral trunk of the sympathetic nervous system and various innervation pathways. These results suggest that trkB may code for a novel cell surface receptor involved in neurogenesis.
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The retinoblastoma gene (Rb) was the first tumor suppressor gene to be cloned [Dryja et al., 1986; Friend et al., 1986; Lee et al., 1987], and, as a consequence, has been studied intensively within the context of cell cycle regulation and oncogenesis. However, a number of recent findings indicate that the retinoblastoma gene product (pRb) likely plays an essential role not only in controlling entry into the cell cycle, but also in the terminal differentiation of a number of different cell types [Lee et al., 1994; Gu et al., 1993]. In particular, the phenotype of the Rb nullizygous mice, created by a number of groups using homologous recombination [Jacks et al., 1992: Clarke et al., 1992; Lee et al., 1992], indicates that pRb is essential for normal development of the nervous and hematopoietic systems and may even function to regulate apoptosis [Haas-Kogan et al., 1995]. Although this paper briefly reviews the traditional role of pRB in regulation of cellular proliferation, we focus on the role of pRB in neuronal development and apoptosis. Recent reviews have been published on the role of pRb in cell cycle and transcriptional regulation [Hamel et al., 1992; Cobrinik et al., 1992; Kouzarides, 1993; Hollingsworth et al., 1993; Helin and Harlow, 1993; Sherr, 1994], as well as the relationship between pRb and p53 [Picksley and Lane, 1994; White, 1994].
A novel aspect of cellular signalling during the formation of the nervous system is the involvement of the messenger molecule nitric oxide (NO), which has been discovered in the mammalian vascular system as mediator of smooth muscle relaxation. NO is a membrane-permeant molecule, which activates soluble guanylyl cyclase (sGC) and leads to the formation of cyclic GMP (cGMP) in target cells. The analysis of specific cell types in model insects such as Locusta, Schistocerca, Acheta, Manduca, and Drosophila shows that the NO/cGMP pathway is required for the stabilization of photoreceptor growth cones at the start of synaptic assembly in the optic lobe, for regulation of cell proliferation, and for correct outgrowth of pioneer neurons. Inhibition of the NOS and sGC enzymes combined with rescue experiments show that NO, and potentially also another atypical messenger, carbon monoxide (CO), orchestrate cell migration of enteric neurons. Cultured insect embryos are accessible model systems in which the molecular pathways linking cytoskeletal rearrangement to directed cell movements can be analyzed in natural settings. Based on the results obtained from the insect models, I discuss current evidence for NO and cGMP as essential signalling molecules for the development of vertebrate brains.
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Even though phosphorylation of phosphatidylinositols by phosphoinositide 3-kinase (PI3K) has an important and pervasive role in the nervous system, there is little known about the phosphatases that reverse this reaction. Such a phosphatase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), was cloned as a tumor suppressor for gliomas. PTEN is expressed in most, if not all, neurons and is localized in the nucleus and cytoplasm. Recently, a series of papers using PTEN conditional knockouts has greatly extended our knowledge of PTEN's role during development. Loss of PTEN results in disorganization of the brain, probably due to a flaw in cell migration. In addition, there is a gradual increase in the size of neuronal soma, mimicking Lhermitte-Duclos disease. Recent experiments in our laboratory with adult PTEN +/- mice demonstrate that PTEN regulates migration of precursor cells in the subventricular zone to the olfactory bulb. We also found that PTEN haploinsufficiency can protect precursor cells from apoptosis in response to oxidative stress. Collectively, these studies demonstrate that PTEN does much more than suppressing tumors. It is a master regulator in developing and adult brain.
We have examined the expression of Thy-1, an abundant glycosylphosphatidylinositol (GPI)-anchored glycoprotein, in dorsal root ganglia (DRG) and associated nerve fascicles, during postnatal development and following a nerve crush. The expression levels of Thy-1 in DRG neurons, dorsal roots, and central processes in spinal cord were rather low at postnatal day 2, and gradually increased as DRG neurons matured. During early development, the expression of Thy-1 within DRG neurons was low and equally distributed between plasma membrane and cytosol. With maturation, the staining intensities of Thy-1 in both the plasma membrane and the cytosol of DRG neurons became increased. We also studied Thy-1 expression in the regeneration of mature DRG neurons following the crush injury of sciatic nerve. Two days after the crush injury, Thy-1 expression dramatically decreased in the DRG neurons on the lesion side. Between 4 and 7 days after the injury, the expression of Thy-1 gradually increased and returned to a normal level 1 week after the sciatic nerve crush. The time course of the up-regulation of Thy-1 expression during regeneration matched that of the recovery of sensory functions, such as pain withdraw reflex, placing reflex, and the score of Basso-Beattie-Bresnahan Locomotor Rating Scale. Taken together, our results suggest that Thy-1 expression is developmentally regulated and is closely associated with the functional maturation of DRG neurons during both postnatal development and nerve regeneration. Furthermore, perturbation of Thy-1 function with anti-Thy-1 antibodies promoted neurite outgrowth from primary cultured DRG neurons, again confirming the inhibitory role of Thy-1 on neurite outgrowth.
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It is feasible to study the anatomical, physiological, and biochemical properties of identifiable neurons in lobster embryos. To exploit fully the advantages of this preparation and to lay the foundation for single-cell studies, our recent goals have been to 1) establish a quantitative staging system for embryos, 2) document in detail the lobster's embryonic development, 3) determine when uniquely identifiable neurons first acquire their transmitter phenotypes, and 4) identify particular neurons that may serve developmental functions. Behavioral, anatomical, morphometric, and immunocytochemical studies have led to a detailed characterization of the growth and maturation of lobster embryos and to the adoption of a percent-staging system based upon the eye index of Perkins (Fish. Bull., 70:95-99, 1972). It is clear from these studies that the lobster nauplius molts at approximately 12% embryonic development (E12%) into a metanauplius, which subsequently undergoes a complete molt cycle within the egg. This molt cycle climaxes with the emergence of the first-stage larva shortly after hatching. Serotonin and proctolin, neurohormones widely distributed in the lobster nervous system, appear at different times in development. Serotonin immunoreactive neurons begin to appear at approximately E10%, with the adult complement being established by E50%. In contrast, proctolin immunoreactive neurons appear later and attain their full complement over a protracted period including larval and juvenile stages. The development of serotonergic deutocerebral neurons and their targets, the olfactory and accessory lobes in the brain, are also examined. The olfactory lobes are forming by E10% and have acquired their glomerular organization by E50%, whereas the formation of the accessory lobes is delayed; the early rudiments of the accessory lobes are seen by E50%, and glomeruli do not form until the second larval stage.
We studied early neurulation events in vitro by transplanting quail Hensen's node, central prenodal regions (before the nodus as such develops), or upper layer parts of it on the not yet definitively committed upper layer of chicken anti-sickle regions (of unincubated blastoderms), eventually associated with central blastoderm fragments. We could demonstrate by this quail-chicken chimera technique that after the appearance of a pronounced thickening of the chicken upper layer by the early inductive effect of neighboring endophyll, a floor plate forms by insertion of Hensen's node-derived quail cells into the median part of the groove. This favors, at an early stage, the floor plate "allocation" model that postulates a common origin for notochord and median floor plate cells from the vertebrate's secondary major organizer (Hensen's node in this case). A comparison is made with results obtained after transplantation of similar Hensen's nodes in isolated chicken endophyll walls or with previously obtained results after the use of the grafting procedure in the endophyll walls of whole chicken blastoderms.
Neuronal growth-associated proteins (nGAPs) are in general neuron-specific gene products whose expression correlates tightly with neuronal process outgrowth and/or regeneration, and are mostly good downstream targets of neurotrophin stimulation. Expression of genes encoding nGAPs such as GAP-43, SCG10, and stathmin is upregulated following lesioning of cortical and hippocampal regions of the adult rat brain. In the brains of aged animals, however, the magnitude of the response is reduced, whereas the time course of the response is mostly unchanged when compared with that for brains of young ones. Expression of GAP-43 and stathmin is reduced by aging, and is also changed in age-related neurodegenerative conditions such as Alzheimer's disease in humans. Certain nGAPs are induced during long-term potentiation (LTP) and also during critical periods of song-learning and ocular dominance column formation in birds and cats, respectively. Recent evidence further supports the idea that functional synaptic modulation is often associated with remodeling of synaptic structures. These results suggest that neurotrophin-responsive nGAPs serve as molecular markers of neuronal plasticity during development and aging, and that the neuronal plasticity decreases, at least in certain neuronal circuits, in the aged brain and neurodegenerative diseases. Recent findings on the roles of stathmin and SCG10-related proteins in microtubule destabilization and its functional block by phosphorylation further support the importance of the SCG10 family proteins in neuronal cytoskeletal regulation, particularly as to microtubule dynamics. We summarize here a decade of research on SCG10 and its related molecules with special interests to brain aging and disease.