Research proposal: Cortical development depends on a sequence of cellular interactions involving growth factors and neurotransmitters. In adult brain, these molecules induce the rapid and transient expression of proteins that may control long-term responses. Analogous novel regulatory genes, induced by synaptic activity and expressed at high levels, at critical periods, in developing cortex were identified in Dr. Worley's laboratory by molecular cloning techniques. Adr-1 encodes a 45 kD protein with homology to spectrin, that appears to be brain specific and expressed during the critical postnatal period, suggesting a link between extracellular stimuli and changes in neuronal morphology. Rasp encodes a GTP-binding protein with homology to ras (40% identity) and rap (45% identity) and is expressed in the prenatal rat cortex. Like ras, rasp transforms NIH3T3 cells, indicating an active role in cellular signalling. The central hypothesis is that physiological activity induces the expression of both adr-1 and rasp and also modulates their intracellular localization. This will be tested, in normal rat cortex, in Aims 1 and 2, respectively. After obtaining this basic framework, a similar study will be performed in two animal models, characterized by decreased cortical input, and relevant for mental retardation: rats with nutritional-environmental deprivation and mice with basal forebrain neonatal lesions (Aims 3 and 4). Environment: Dr. Kaufmann's activities will be in the context of the Mental Retardation Center, which comprises several research groups studying different aspects of development relevant to mental retardation such as gene expression in brain development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD001046-02
Application #
2194589
Study Section
Mental Retardation Research Committee (HDMR)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kaufmann, W E; MacDonald, S M; Altamura, C R (2000) Dendritic cytoskeletal protein expression in mental retardation: an immunohistochemical study of the neocortex in Rett syndrome. Cereb Cortex 10:992-1004
Haydar, T F; Nowakowski, R S; Yarowsky, P J et al. (2000) Role of founder cell deficit and delayed neuronogenesis in microencephaly of the trisomy 16 mouse. J Neurosci 20:4156-64
Kaufmann, W E; Reiss, A L (1999) Molecular and cellular genetics of fragile X syndrome. Am J Med Genet 88:11-24
Abrams, M T; Kaufmann, W E; Rousseau, F et al. (1999) FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome. Am J Med Genet 82:25-30
Kaufmann, W E; Worley, P F; Taylor, C V et al. (1997) Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome. Brain Dev 19:25-34
Kaufmann, W E; Taylor, C V; Hohmann, C F et al. (1997) Abnormalities in neuronal maturation in Rett syndrome neocortex: preliminary molecular correlates. Eur Child Adolesc Psychiatry 6 Suppl 1:75-7
Kaufmann, W E; Taylor, C V; Lishaa, N A (1997) Immunoblotting patterns of cytoskeletal dendritic protein expression in human neocortex. Mol Chem Neuropathol 31:235-44
Kaufmann, W E; Worley, P F; Pegg, J et al. (1996) COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A 93:2317-21