Damage to the developing or mature nervous system can be devastating due to the limiting ability of central nervous system axons to regenerate if they are severed. Two laboratories in the IDDRC (Benowitz and Z. He) have made outstanding contributions to the understanding of the molecular basis of the barriers to axon re-growth after injury and are moving toward the development of potential therapies for promoting the effective re-growth of axons to restore function in the injured nervous system. A focus of this research has been to identify the components in myelin that are inhibitory to re-growth. Work by Zhigang He and his colleagues have identified a new component of ...
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During the development of the nervous system there is a critical balance between the survival and death of developing neurons. Neurons that form the proper connections received trophic support from their targets and survive whereas neurons that fail to compete effectively for target derived neurotrophic factors die by a process of programmed cell death termed apoptosis. Research over the last decade had defined the molecular underpinnings of the apoptotic process, but the molecular mechanisms by which target derived neurotrophic factors suppress apoptosis and promote survival were unknown. Investigators in this IDDRC have made outstanding contributions to the understanding of ...
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Beginning in 1991, a major new area of research in this IDDRC has been the study of neural progenitor or “stem cells.” This research has included landmark studies of cell fate determination (i.e., identification of external factors and instrinsic factors that regulate the differentiation of neural progenitor cells into neurons, astrocytes and oligodendrocytes). Dr. Greenberg and his colleagues demonstrated that cilliary neurotrophic factor acting through the Jak/STAT pathway plays a key role in the generation of astrocytes (see Science 1997). Drs. Stiles and Rowitch have carried out seminal work leading to the discovery of a family of transcription factors (
A critical early contribution of Greenberg and his colleagues was the development of phosphorylation site-specific antibodies to CREB. With these phospho-CREB specific antibodies, they were able to show that synaptic activity within the brain triggers CREB activation. This provided the first evidence that the signal transduction pathways that had been implicated in the induction of activity-regulated genes in cell culture were also activated by neuronal activity in live animals. Perhaps more importantly, this study was among the first to demonstrate the utility of phospho-specific antibodies for studying signal transduction pathways within ce...
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In the 1980s Dr. Greenberg and his colleagues discovered that neuronal activity induces a genetic program that plays a key role in mediating brain development and function (Science 1986). Recent evidence from the laboratory indicates that mutations in components of the signaling network that regulates this gene program can lead to profound disruptions of cognitive function resulting in mental retardation and possibly autism. Over two decades, and under the auspices of the IDDRC since 1994, this laboratory has studied the activity-regulated gene program in considerable detail. Greenberg and his colleagues identified a signaling network that conve...
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In the last decade investigators in this IDDRC have made exceptional use of human genetics to identify genes that cause neurological disorders. Dr. Christopher Walsh has been a pioneer in identifying genes that control the development and function of the human cerebral cortex whose mutation can cause autism and epilepsy as well as mental retardation and other learning disorders. Using human genetics to study Middle-Eastern families with a high incidence of disorders of cognitive function Dr. Walsh and his colleagues are making rapid progress in identifying new genes that control the development of human cognition. These genes include those whose mutation causes Joubert syndrome, bil...
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Wnts are secreted proteins that play critical roles in mammalian brain development and function. During embryogenesis, Wnt genes not only control brain patterning and neuronal progenitor proliferation and differentiation, but also regulate axon pathfinding and synapse formation. Wnt genes also govern the proliferation of adult neural stem cells. Dr. Xi He’s laboratory in this IDDRC has made groundbreaking progress in charactering the mechanisms of Wnt signal transduction. Among their discoveries are: (1) the demonstration that the LDL receptor-related proteins, LRP5 and LRP6, are co-receptors for the canonical Wnt/beta-catenin signaling pathway and (2) the finding that t...
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Morphogenesis, the process of cellular organization, determines the form and function of the organs. A relatively few cellular behaviors are responsible for all of morphogenesis: these include changes in cell shape, motility, adhesion, proliferation and differentiation. These changes are initiated, controlled and integrated by effectors in a cell’s microenvironment, especially extracellular matrix components, growth factors, cell surface proteins, proteases and anti-proteases. Cell surface receptors mediate the action of these effectors and mutations in these molecules and their receptors can cause abnormalities in morphogenesis. The CNS is the first organ system to undergo morphoge...
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The important role of glutamate as the mediator of neuronal cell death by receptor-mediated mechanisms that involve the accumulation of cytosolic calcium was established primarily in the 1980's by work in several laboratories, including those of Drs. Stuart Lipton and Paul Rosenberg in this IDDRC. In 1989, Rosenberg demonstrated the crucial role of astrocytes in the modulation of neuronal vulnerability to glutamate. Thus Rosenberg demonstrated a 100-fold increase in neuronal vulnerability to glutamate when neurons were grown in culture in the absence of astrocytes (Neurosci. Lett., 1989). Rosenberg was able to define the intrinsic vulnerability of neurons to glutamate and demonst...
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A series of studies led by Dr. Marc Lalande, formerly of this IDDRC, delineated the regions on chromosome 15q11-13 that are mutated in Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Lalande’s research also identified candidate genes in these regions and provided important insights into how an abnormality in genetic imprinting can lead to mental retardation (Am. J. Hum. Genet., 1991; Genomics, 1991; Lancet, 1992; Nature Genetics, 1992; Hum. Molec. Genet., 1993; Am. J. Med. Gen., 1993; Nature Genetics, 1994; Am. J. Med. Gen., 1994). The majority of the AS and PWS patients display a cytogenetic deletion o...
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In 1984 and 1985, Kurnit and coworkers reported that Down's syndrome cells from developing lungs and hearts are more adhesive to each other than are the cells of normal controls (Am. J. Med. Gen., 1985; Proc. Natl. Acad. Sci., 1984). They also showed by computer simulations how such increased adhesiveness could result in the congenital lung and heart defects that are characteristically seen in Down's syndrome. Subsequent work in this IDDRC has discovered families of cell adhesion proteins important in neural development. An important relationship between Alzheimer's disease and Down's syndrome was established with the demonstrations that patients with Down's syndro...
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Of the 30,000 infants born annually in the United States with congenital heart disease, more than one-third will require cardiac surgery in the neonatal period. Dramatic reductions in surgical mortality for such deep hypothermic cardiac surgery with cardiopulmonary bypass have been accompanied by the recognition that the survivors frequently experience adverse neurological sequelae, including cognitive deficits and other developmental disabilities. The majority of such brain injury appears to be attributable to operative events, particularly the cardiopulmonary support systems used to protect vital organs during cardiac repair. From the early 1990's a major program in this IDDRC has focus...
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Medulloblastomas and other embryonal brain tumors, the most common malignant brain tumors of childhood, have a 40-50% overall mortality. Survivors typically live with profound developmental and neurological disabilities, largely due to toxic therapies currently in use. In 1994, the Pomeroy lab was the first to show that a molecular marker, the neurotrophin-3 receptor TrkC, can predict overall survival of embryonal tumors with significantly greater accuracy than clinical or histological features. The group, then, was the first to apply genomic methods to show that favorable prognosis tumors have substantially different gene expression profiles than poor prognosis tumors, identifying a mole...
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This research, which developed most actively in the mid-1980's and continues vigorously to the present, has been led in a most remarkable way by Dr. Louis Kunkel, Director of the Genetics Program and Associate Director of this IDDRC. Duchenne muscular dystrophy is a severe X-linked dystrophic myopathy; Becker muscular dystrophy is a phenotypically less severe disorder. In Duchenne muscular dystrophy a cognitive disturbance is present in all patients, such that as a group, IQ is distributed in a bell-shaped fashion but with a distinct shift of the curve to the left. The accomplishments of Kunkel and co-workers in the years leading to the 1995 renewal of this IDDRC were of profound importan...
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The two major forms of brain injury in premature infants are periventricular leukomalacia (PVL) and periventricular hemorrhagic infarction (PHI), a form of severe germinal matrix/intraventricular hemorrhage (GMH-IVH). Research in this IDDRC from the early 1990's to the present has addressed the pathogenesis of this injury in living infants and the mechanisms of cell death of the cellular target in white matter, the developing oligodendrocyte. The research was carried out primarily by Drs. Volpe, du Plessis and Rosenberg and represents a stunning example of how the IDDRC has fostered research that ranges all the way from the bedside to the laboratory bench (for key initial work see <...
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Beginning in the mid-1970's, the IDDRC at Children's Hospital became the site of a multidisciplinary longitudinal study of the adverse effects of concentrations of lead below previously accepted exposure levels. Drs. Alan Leviton and David Bellinger were the key figures in that work. The results indicated that lead has an adverse biological effect at much lower levels than those previously thought to be acceptable and that the adverse effects do not improve with time (Genetics Resource, 1988; Research in Infant Assessment, 1989; N. Engl. J. Med., 1990). These and other studies resulted in a national effort to reduce environmental lead, and over the years the l...
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Stimulated by the original observations of Mabry and his colleagues in the early 1960's, Dr. Harvey Levy in this IDDRC had a central role in the study of the effect of untreated maternal PKU during pregnancy on the offspring (Transplacental Effects on Fetal Health, 1988). An international survey found that when mothers had classic PKU and their pregnancies were untreated, 92% of the offspring were mentally retarded. In a further followup study of 435,000 women screened in Massachusetts, Levy identified 22 with persistent hyperphenylalaninemia; two of these women had classic PKU and all four of their children were adversely affected. Of the remaining 20 with atypical PKU or non-P...
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Observations reported in the mid-1980's described the occurrence of cognitive impairments subsequent to prophylactic cranial radiation in children with leukemia. Waber and her collaborators in this IDDRC followed up on this initial observation (Dev. Med. Child Neurol., 1990). Cognitive function and physical growth were measured in 51 children who had been treated for acute lymphoblastic leukemia with the combination of chemotherapy, cranial radiation and intrathecal methotrexate and were continuously disease-free for 5 to 12 years. A comparison group of children treated for a solid tumor, Wilms tumor, also was studied. The rates of cognitive impairment and growth retardation were...
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As an early effort at what might be regarded as "genetic engineering" in the mid 70's, Richard Mullen of the Neuroscience Program of the IDDRC developed the skill of combining eight-cell-stage rodent embryos from genetically normal and abnormal individuals to produce surviving chimeras (Science, 1976; Nature, 1977). This approach was applied to the study of animals with neurological abnormalities, one with retinal degeneration and visual disturbance, and the other, with cerebellar Purkinje cell degeneration and clinical ataxia. In both instances, the clinical disorder was ameliorated in the chimera. The principal value of the experiment was the resulting ability t...
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Retinal disease that causes deficits of central and peripheral vision in infants and young children is a recognized accompaniment of several disorders in which mental retardation and developmental disability are also prominent and is an independent cause of developmental disturbances. Young age and limited abilities had interfered with quantitative assessment of visual acuity, retinal sensitivity and retinal adaptor processes in these patients. Dr. Ann Fulton developed procedures that depend on modifying the child's looking behavior with visual stimuli and used these methods to begin evaluation of visual function in children with recognized retinal and brain disorders. Using these procedu...
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Several investigators of the IDDRC (Duffy, Snodgrass, Burchfiel, Nature, 1976) showed that the GABA antagonist, bicuculline, can reverse the inhibition of a significant percentage of the inactive nerve cells in the visual cortex in an experimental model of amblyopia. This study revealed that these inactive cells were undergoing active inhibition that could be reversed. The ability to reverse this inhibition provided avenues for developing therapies for treating amblyopia and possibly other neurologic disorders. These finding may be relevant to the understanding of "critical periods" of neuronal plasticity. Related studies of neurophysiological development and plasticity con...
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Between approximately 1980 and 1990, major insights into the relationships between the sex chromosomes and behavior were established by interactions in the Children's Hospital IDDRC between investigators in the Genetics Program and in the Clinical/Translational Neuroscience Program. Three major groups of patients were studied, i.e., XXY and XYY males, fragile X males, XO females. The behavioral profile in XXY and XYY males was established by studies of Dr. Stanley Walzer (Department of Psychiatry) and Dr. Gerald Parks (Division of Genetics, Department of Medicine) in this IDDRC in the late 1980's (Birth Defects Original Article Series, 1990). The 47 XXY boys evidenced a continuu...
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In the late 1970's and early 1980's the mutant mouse, Spastic, was studied to determine the origin of its neurological syndrome of tremors and abnormal righting behavior. An electrophysiological analysis suggested a deficit in inhibition at the level of the spinal cord, and treatment of normal mice with strychnine, which blocks glycinergic inhibition, caused these mice to mimic the behavior of the Spastic mice. Chemical studies then demonstrated that the Spastic mouse appears to have an absolute deficit in glycine receptors in the spinal cord and brainstem, despite normal receptor numbers for several other neurotransmitters. Thus, the work of White and Heller with this mutant was the firs...
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Periventricular white matter injury is the most important neuropathological substrate for the subsequent neurological disability, i.e., cerebral palsy and cognitive deficits, observed in premature infants. In 1973 Leviton and Gilles began a classic series of neuroepidemiologic and neuropathologic studies linking bacteriemia and endotoxin to the cause of this type of injury (J. Neurol. Sci., 1973; Ann. Neurol., 1984; J. Neurol. Sci., 1976; The Developing Brain: Growth and Epidemiologic Neuropathology, 1983). Subsequent work showed that ischemia also is crucial in pathogenesis of this injury. The work of Leviton and Gilles led to the later discovery of...
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In the early 1970's, Cutler, Lorenzo, Barlow and their colleagues (Brain, 1968; Brain, 1970; Arch. Neurol., 1974) carried out fundamental studies of infants with hydrocephalus which provided much of the current knowledge of cerebrospinal fluid (CSF) production and absorption. By adapting the ventricular-lumbar perfusion technique to study of humans these investigators made a series of quantitative studies of CSF formation and absorption. The normal rate of CSF formation was measured and was found to be essentially unchanged in human hydrocephalus, except in choroid plexus papilloma where CSF formation was greatly increased. The absorption of CSF was shown to be...
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The important observation of neuronal retrograde transport of horseradish peroxidase in the central nervous system by the LaVails in 1972 had a profound impact on neuroanatomy and neurobiology in the decades following the description of this phenomenon (Science, 1972). This fundamental observation has had widespread use as a tool to establish anatomically interconnected areas of brain, and provided the seminal insight that nerve cell processes can sample the chemical environment and transport materials great distances back to the cell body. Current IDDRC research that emanates from this historical work have identified signal transduction mechanisms that involve the ra...
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The study of human chromosomes was pursued actively by Dr. Samuel Latt over the many years of his tenure in the Children's Hospital IDDRC (Ann. Rev. Biophys. Bioengr., 1976; Ann. Rev. Gen., 1981; Banbury Report, Cold Spring Laboratory, 1983). Latt was initially recruited as a "new investigator" in the Center and before his untimely death had risen to become the Director of the IDDRC Genetics Program. From early work with DNA binding dyes, which stained different regions of human chromosomes, Latt developed methods that enabled him to follow the replication pattern of DNA within the chromosome. This interest in DNA binding dyes and newly developed means to dete...
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In the 1970's Rakic, Sidman and co-workers in this Center defined the mechanisms of neuronal migration during development of the mammalian cerebral cortex (J. Comp. Neurol., 1972; Science, 1974; J. Comp. Neurol., 1973). Radial glial fibers were discovered and shown to be the major guides of neuronal migration. The research indicated that sequential generations of cells originating in the germinative ventricular zones migrated in waves along these fibers, and that ultimately migrating neurons generated earliest in development reside in the deepest layers in cerebral cortex and neurons generated later reside in progressively more superficial layers, result...
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