Mark F. Mehler

Cytokine regulation of neuronal differentiation of hippocampal progenitor cells

THE signalling mechanisms governing haematolymphopoiesis and those regulating neural development may be closely related, as indicated by similarities of higher-order structure and function of the cytokines involved1, of the regional and temporal regulation of their transcription and translation2–6, and of their bioactivity7–10. Here we investigate this possible evolutionary connection using retroviral transduction of a temperature-sensitive mutant form of the SV40 large T antigen to develop conditionally immortalized murine embryonic hippocampal progenitor cell lines11–14. Treatment of these cells with cytokines that are thought to participate in progressive lymphoid maturation, immunoglobulin synthesis15–18 and erythropoiesis19,20 causes progressive neuronal differentiation, as defined by morphological criteria, successive expression of increasingly mature neurofilament proteins21–23, and the generation of inward currents and action potentials. The cytokine interleukin(IL)-11 induces expression of action potentials that are insensitive to tetrodotoxin, which is indicative of develop-mentally immature sodium channels24. By contrast, for expression of more mature action potentials24 (tetrodotoxin-sensitive) one of the interleukins IL-5, IL-7 or IL-9 must be applied in association with transforming growth factor-α after pretreatment with basic fibroblast growth factor. Our results suggest that the mechanisms regulating lineage commitment and cellular differentiation in the neural and haematopoietic systems are similar. Further, they define an in vitro model system that may facilitate molecular analysis of graded stages of mammalian neuronal differentiation.

Developmental Changes in Progenitor Cell Responsiveness to Bone Morphogenetic Proteins Differentially Modulate Progressive CNS Lineage Fate

Although multipotent progenitor cells capable of generating neurons, astrocytes and oligodendrocytes are present within the germinal zones of the brain throughout embryonic, postnatal and adult life, the different neural cell types are generated within discrete temporospatial developmental windows. This might suggest that multipotent progenitor cells encounter different signals during each developmental stage, thus accounting for separate waves of lineage commitment and cellular differentiation. This study demonstrates, however, that progenitor cell responses to the same class of signals, the bone morphogenetic proteins (BMPs), change during ontogeny, and that these same signals may thus initiate progenitor cell elaboration of several different lineages. BMPs promote cell death and inhibit the proliferation of early (embryonic day 13, E13) ventricular zone progenitor cells. At later embryonic (E16) stages of cerebral cortical development, BMPs exhibit a concentration-dependent dissociation of cellular actions, with either enhancement of neuronal and astroglial elaboration (at 1–10 ng/ml) or potentiation of cell death (at 100 ng/ml). Finally, during the period of perinatal cortical gliogenesis, BMPs enhance astroglial lineage elaboration. By contrast, oligodendroglial lineage elaboration is inhibited by the BMPs at all stages. Further, application of the BMP antagonist noggin to cultured progenitors promotes the generation of oligodendrocytes, indicating that endogenous BMP signaling can actively suppress oligodendrogliogenesis. These observations suggest that developmental changes in neural progenitor cell responsiveness to the BMPs may represent a novel mechanism for orchestrating context-specific cellular events such as lineage elaboration and cellular viability.

Growth Factor Regulation of Neuronal Development

Recent experimental investigations have redefined the spectrum of growth factors and developmental signalling pathways that are necessary to orchestrate the growth and differentiation of regional neuronal subpopulations. Gene knockout studies of the classic neurotrophins and their high-affinity tyrosine kinase (Trk) receptors have refined our definition of the cellular mechanisms and target populations of these neuronotrophic factors. Recognition of the significant parallels that exist between neuropoiesis and hematolymphopoiesis has fostered our study of the range and cellular actions of these hemopoietins in neuronal development. In addition, by activating receptor subunits that possess serine/threonine activity, bone morphogenetic proteins of the transforming growth factor-beta superfamily exhibit complex spatiotemporal regulation of regional neuronal subpopulations. These collective observations suggest that a complex hierarchy of epigenetic signals is required for the growth and maturation of regional neuronal lineage species in the central and peripheral mammalian nervous system.

Reduced somatostatin‐like immunoreactivity in cerebral cortex in nonfamilial dysphasic dementia

A nonfamilial syndrome is described in two middle-aged men who presented with progressive aphasia without incipient signs of cognitive impairment. In each case, 2 years elapsed before progressive functional decline or behavioral disabilities supervened. Radiologic studies documented asymmetric left cerebral atrophy that was progressive. The structure of the language disintegration was distinctive and not like that in Alzheimers disease. Pathologic studies performed at postmortem examination of one patient documented asymmetric cerebral atrophy with nonspecific histopathologic changes. Biochemical studies revealed normal tissue levels of choline acetyltransferase activity, but reduced somatostatin-like immunoreactivity. Since cerebral somatostatin is largely present in intrinsic cortical neurons, while cholinergic innervation is largely derived from the basal forebrain, these findings suggest that nonfamilial dysphasic dementia may be an example of a distinct class of dementia due to intrinsic cortical degeneration, with sparing of the basal forebrain.

Epigenetics, Nervous System Tumors, and Cancer Stem Cells

Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors.

Animal extremists' threats to neurologic research continue Neuroreality II

In 1995, Landau et al.1 documented the prevailing threats to animal research in “Neuroreality I,” which emphasized the importance of incorporating an understanding of biomedical research within the educational system. Two decades later, the threat against research involving animals has not receded but rather has escalated. It is therefore time to revisit these important issues. According to the Foundation for Biomedical Research, illegal incidents against researchers using animals rose from 6–27 events per year (1993–1997) to 76–103 per year (2003–2006).2 This has occurred against the backdrop of exponential growth in neuroscience research and understanding of neurologic disease pathogenesis leading to innovative treatment strategies. These advances have occurred as a direct outgrowth of the seminal contributions of animal investigations. Therefore, the alarming trend of these direct attacks requires an appropriate response.

The Genetic Basis of Sleep and Sleep Disorders: Epigenetic basis of circadian rhythms and sleep disorders

There has been a significant increase during the last decades in knowledge of genetics of sleep and sleep disorders, and the genetic epidemiologic studies have considerably contributed to this progress in understanding their basis. The primary goal of genetic epidemiology is the resolution of the genetic architecture of a trait, such as sleep length or a disorder. Electroencephalogram (EEG), a parameter included in polysomnography (PSG), has been found to be one of the most heritable characteristics, with heritability estimates greater than 95%, in a sample of 10 MZ and 10 DZ twin pairs. Most studies indicate that certain sleep problems in childhood are largely influenced by genes. Most parasomnias are relatively common to very common in childhood, occurring clearly less frequently in adults. Clinical experience and many studies indicate that parasomnias are often found to co-occur and run in families.

Hematolymphopoietic and Associated Cytokines in Neural Development

Ithas become increasingly apparent that many of the same factors regulate development of both the nervous and hematolymphoid systems. Members of two cytokine superfamilies, the hemopoietins and the transforming growth factor βs (TGFβs), and the more recently characterized glial cell-derived neurotrophic factor (GDNF) family, mediate a complementary range of developmental events in the nervous system that frequently exceed those mediated by the classic neurotrophins (Table 1.1). These cytokine families, which are active in hematolymphoid development, are also involved in neurulation, dorsoventral patterning of the neural tube, and in the progressive evolution of the mammalian central and peripheral nervous systems. Recent studies have begun to characterize the detailed receptor subunit organization and the intracellular signaling pathways utilized by these growth factor families, the specific environmental contexts in which they act and the range of cellular processes by which they orchestrate the progressive sculpting of the developing nervous system. In addition, several experimental investigations have presented provocative evidence suggesting a role for these cytokines in modulating a range of developmental events through bidirectional communications between the hematolymphoid and neural systems.1−4 These diverse cytokines exhibit significant functional redundance and pleiotropy, especially during brain development; thus, targeted knockouts of cytokine signaling components generally demonstrate few central nervous system deficits, although there are often significant developmental abnormalities in the peripheral nervous system.