C. Dominique Toran Allerand, M.D., Sc.D. h.c.

Professor

E-mail: cdt2@columbia.edu

RESEARCH INTERESTS: Dr. Toran-Allerand studies how the steroid hormone estrogen and the neurotrophin family of growth factors interact in controlling the differentiation and survival of their target neurons in the developing CNS. These investigations test her hypothesis that estrogen is an important neurotrophic factor throughout life and that estrogen action in developing, as well as injured, diseased or aging brain regions, may involve interactions with the neurotrophins and their receptors. Understanding how estrogen influences differentiation and development in the CNS through its interactions with the neurotrophins may help explain recent findings that (i) estrogen can exert effects on higher order cognitive processes and (ii) that estrogen or its deficiency may be risk factors for the development of the sexually dimorphic disorders of cognition, such as (a) learning disabilities, (b) infantile autism, (c) delayed speech acquisition and (d) the attention deficit disorders; (e) neurodevelopmental disorders with cognitive deficits, such as schizophrenia and Turner's syndrome; and (f) neurodegenerative disorders, such as Alzheimer's disease. Estrogen receptors and estrogen signaling in the developing CNS. The long-term goals of the research in my laboratory are to understand the cellular and molecular mechanisms underlying the growth- or neurite-promoting properties of estrogen, which I first described in organotypic slice cultures of the developing rodent hypothalamus, preoptic area and neocortex. My current studies investigate some novel sites and mechanisms that may underlie the developmental actions of estrogen in forebrain neurons that subserve cognitive functions. Our recent findings in neurons of the developing neocortex document (i) estrogen-induced activation of the MAP kinase cascade, a major growth factor signaling pathway involved in neuronal differentiation and neuronal survival; (ii) a putative, novel, membrane-associated estrogen receptor (ER) ("ER-X") that may mediate some rapid [non-genomic (non-DNA-mediated)] effects of estrogen, including activation of the MAPK cascade; and (iii) similarities and differences in the estrogen and growth factor (neurotrophin) signal transduction pathways, particularly at the level of the MAP kinase cascade. We have been characterizing estrogen-induced signal transduction pathways and the structural and functional characteristics of "ER-X". We study organotypic explant (slice) cultures of the developing rat forebrain and clonal neural (PC12; SK-N-SH) and non-neural cell lines (MCF-7; COS; CHO). We use a combination of histological, molecular biological and biochemical techniques to study transcription, translation and cell signaling and neuronal differentiation. Morphological findings are correlated with functional output, using sensitive quantitative measures of estrogen binding, signaling, gene transcription/translation. These investigations test my hypothesis that estrogen is an important neurotrophic factor throughout life and that estrogen action is important not only in the developing brain, but in injured, diseased or aging brain regions as well as. Understanding how estrogen influences differentiation and development in the CNS may help explain recent findings that (i) estrogen can exert effects on higher order cognitive processes and (ii) that estrogen or its deficiency may be risk factors for the development of the sexually dimorphic disorders of cognition, such as (a) learning disabilities, (b) infantile autism, (c) delayed speech acquisition and (d) the attention deficit disorders; (e) neurodevelopmental disorders with cognitive deficits, such as schizophrenia and Turner's syndrome; and (f) neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, and stroke. Selected publications Nethrapalli NS, Singh M, Guo QF, Guan X, Lubahn DB, Korach KS and Toran-Allerand CD (2001) Estrogen Elicits Src Phosphorylation in Mouse Neocortical Explants: An Upstream Event in Estrogen Activation of the MAP Kinase Cascade. Endocrinology, (in press) Toran-Allerand CD (2001) Interactions of estrogen with the neurotrophins and their receptors. In Neurobiology of the Neurotrophins, I. Mochetti, ed., F.P Graham Publishing Co, Johnson City TN, 607-630. Toran-Allerand CD (2000) Novel sites and mechanisms of estrogen action in the brain. In: Neuronal and Cognitive Effects of Oestrogens, Wiley, Chichester (Novartis Foundation Symposium 230) (pp. 56-73). Singh M, Sétáló Jr. G, Guan X, Frail DF, Toran-Allerand CD (2000). Estrogen-induced Activation of the MAP Kinase Cascade in the Cerebral Cortex of Estrogen Receptor-a Knock-out (ERKO) Mice. J. Neurosci. 20 1694-1700. Singh M, Sétáló Jr. G, Guan X, Warren M, Toran-Allerand CD (1999) Estrogen-induced Activation of MAP Kinase (ERK) in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways. J. Neurosci., 19 1179-1188. C. Dominique Toran-Allerand's Medline citations