Reelin glycoprotein is a serine protease with important roles in embryogenesis and during adult life. This comprehensive and integrative book examines the role that reelin plays in the etiology of various neuropsychiatric disorders, including schizophrenia and autism. The book provides an unprecedented analysis of this emerging and novel protein by examining evidence from genetic, neuroanatomic, biochemical, and behavioral studies.

The end of neurogenesis in the human brain is marked by the transformation of the neural progenitors, the radial glial cells, into astrocytes. This event coincides with the reduction of Reelin expression, a glycoprotein that regulates neuronal migration in the cerebral cortex and cerebellum. A recent study showed that the dentate gyrus of the adult reeler mice, with homozygous mutation in the RELIN gene, have reduced neurogenesis relative to the wild type. Based on the above findings, our first hypothesis states that Reelin expression is important for the formation of radial glia and the generation of neurons from the neural progenitors. In order to investigate the role of Reelin in the process of cortical neurogenesis during development, we used human neural progenitor cells (hNPCs) that were isolated from a fetal cortex. These cells do not express Reelin. In this study, we show that Reelin addition to these hNPCs in vitro induced the formation of radial glia and increased neurogenesis significantly. Next, we investigated the mechanism by which Reelin increases the formation of radial glia and the generation of neurons. The formation of radial glia is under the control of two pathways, these are the Reelin and the Notch-1 signaling pathways. Since the level of Notch-1 activation determines if a cell would become a radial glia or an astrocyte, and since the absence of Reelin allows the transformation of a radial glia into astrocyte, we hypothesized that Reelin induces the formation of radial glia via activating Notch-1 signaling. To test this hypothesis, we investigated the effect of Reelin addition on Notch-1 activation in hNPCs. We found that Reelin addition in vitro activated Notch-1 signaling by increasing the level of Notch-1 intracellular domain (NICD). On the other hand, reducing NICD release, by inhibiting [gamma]-secretase activity, inhibited the Reelin-induced radial glia, confirming that Reelin's effect on the formation of radial glia is dependent on Notch-1 activation. Furthermore, we found that the Reelin-induced tyrosine phosphorylation of Disabled-1 (Dab-1), an adaptor protein downstream of Reelin, and the subsequent activation of Src family kinases, are essential steps for Notch-1 activation by Reelin. Finally, we found that Reelin addition increased the binding of Dab-1, recently identified as a nucleoshuttling protein, to NICD and enhanced NICD translocation to the nucleus. This resulted in the induction of BLBP expression and the subsequent formation of radial glia. Taken together, these data show that Reelin signaling, mediated by Dab-1 and Src kinase, activates Notch-1 signaling in hNPCs resulting in the induction of BLBP expression, the formation of radial glia and the generation of neurons. This work is novel because it provides that first evidence that Reelin expression is an important signal for the neuronal differentiation of the hNPCs. It also shows the crosstalk between Reelin and Notch-1 signaling, two major pathways in development and cell fate determination. The work is significant because it improves our understanding of the role of Reelin signaling in cell fate determination, differentiation and neurogenesis for the future manipulation of these processes to restore adult brain functions after brain injury or in neurodegenerative diseases.

Gamma-aminobutyric acid (GABA) was discovered in the brain in 1950 by Eugene Roberts. GABA is now considered one of the most important neurotransmitters and developmental signals. Knowledge on the complexity of GABA function is increasing exponentially. This volume covers basic research on GABA in the developing brain as it may relate to onset of autism and related developmental disorders. The evidence that dysfunction of GABA and related molecules is associated with autism is limited but expanding and seems to converge. Pertinent data are reviewed in this book and new research avenues in the basic and clinical arenas are described. The topics are of imminent interest to basic and clinical researchers as well as interested clinicians. * Discusses the neuropathology of the GABA system in autism * Presents new findings on common genetic mechanisms in Rett syndrome, Angelman syndrome, and autism * Includes information on the shared genetic risk factors between autism and major mental disorders * Foreword by Eugene Roberts

Our understanding of the molecular mechanisms involved in mammalian brain development remains limited. However, the last few years have wit nessed a quantum leap in our knowledge, due to technological improve ments, particularly in molecular genetics. Despite this progress, the available body of data remains mostly phenomenological and reveals very little about the grammar that organizes the molecular dictionary to articulate a pheno type. Nevertheless, the recent progress in genetics will allow us to contem plate, for the first time, the integration of observation into a coherent view of brain development. Clearly, this may be a major challenge for the next century, and arguably is the most important task of contemporary develop mental biology. The purpose of the present book is to provide an overview that syn thesizes up-to-date information on selected aspects of mouse brain devel opment. Given the format, it was not possible to cover all aspects of brain development, and many important subjects are missing. The selected themes are, to a certain extent, subjective and reflect the interests of the contributing authors. Examples of major themes that are not covered are peripheral nervous system development, including myelination, the development of the hippocampus and several other CNS structures, as well as the developmental function of some important morphoregulatory molecules.

Only five years ago, nobody in his right mind would have consid ered publishing a book on reeler as a model for brain develop ment. Although this interesting mutation has been with us for half a century, it is fair to say that, in spite of a wave of enthusiasm in the late sixties and early seventies, generated primarily by Sidman, Caviness and colleagues, studies of reeler mice fell pro gressively out of fashion during the next two decades. All that changed almost overnight when the cloning of the reeler gene, dubbed reelin, was reported in Tom Curran's laboratory in 1995. The fact that the same gene was identified at the same time independently by two other groups using positional cloning sug gested strongly that reelin was the right candidate. Although the key experiments of transgenic rescue have not been made (and perhaps will never be), the equation "reeler is reelin" has been established beyond reasonable doubt, as alterations of the reelin gene and/or its expression have been found in at least five alleles of reeler and in the mutation Shaking Rat Kawasaki (SRK), an ortholog of reeler.

Please note that the content of this book primarily consists of articles available from Wikipedia or other free sources online. Pages: 176. Chapters: Reelin, GRB2, P53, BRCA1, Perlecan, Insulin, Mammalian target of rapamycin, Androgen receptor, Oxytocin, Survivin, Duffy antigen system, HDAC1, Leptin, Proliferating cell nuclear antigen, PTPRM, CREB-binding protein, 5-HT1A receptor, SULF1, Cystatin C, Mir-155, 5-HT2A receptor, EP300, BRCA2, Epidermal growth factor receptor, Retinoblastoma protein, Secreted frizzled-related protein 1, C-Raf, Discovery and development of mTOR inhibitors, C-Met, H19 (gene), PTK2, Protein C, Beta-catenin, Estrogen receptor alpha, 5-HT2C receptor, CBL (gene), Osteopontin, Vasopressin, Antithrombin, Glucokinase, -opioid receptor, FYN, Prostate-specific antigen, Adenosine A2A receptor, Lipoprotein(a), Alpha-synuclein, Aryl hydrocarbon receptor, Amyloid precursor protein, Insulin-like growth factor 1, CYR61, S100A10, Ubiquitin C, Deleted in Colorectal Cancer, Sonic hedgehog, Lactoferrin. Excerpt: Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell-cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the spinal cord, blood, and other body organs and tissues. Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain as...