department of pharmacology

Ruth Siegel, Ph.D.

Siegal

Professor
Director of the Pharmacological Sciences Consortium Core Image Analysis Facility

Phone: (216) 368-5554
Fax: 216-368-1300
E-mail: ruth.siegel@case.edu
W309C Wood Building

Research

Our research seeks to understand events that regulate the postnatal differentiation of the rat cerebellum. Unlike most of the brain, this region differentiates extensively during the first three weeks of life. During this time, cells at the cerebellar cortex divide and then migrate inward to form the mature cerebellum.

A major focus of our studies is the onset and expression of the GABA A receptor during cerebellar development. This multifunctional receptor mediates the actions of ?-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, as well as many clinically important compounds (e.g., Librium and Phenobarbital). The receptor is composed of five subunits, most of which are encoded by gene families. Our studies on cerebellar granule neurons in vivo and in culture have provided insights into receptor gene expression and assembly during postnatal ontogeny. Our findings demonstrate that the eight receptor subunits expressed by cerebellar granule neurons are differentially regulated. Furthermore, subunit polypeptide expression is controlled both at the level of the mRNA and during assembly into cell surface receptors. While the d subunit transcript is induced by depolarization-dependent Ca 2+ influxes, other subunit mRNAs increase in response to extrinsic developmental cues. Most notably, expression of the ß2 subunit, which confers sensitivity to GABA, is induced by neuregulin, a growth and differentiation factor. The effects of neuregulin on granule neuron development and the mechanism of its action is a major focus of current research.

A second major focus of our research is the molecular mechanisms that regulate postnatal cerebellar differentiation. We recently found that bone morphogenetic protein 4 (BMP4), a growth and differentiation factor, is expressed in the postnatal cerebellum and that it induces the differentiation of both cerebellar granule neurons and astrocytes in culture. Moreover, BMP4 activates a number of genes to regulate these changes. In current studies, we are investigating the actions of these BMP4-activated genes in the differentiation of neurons and astrocytes. Our use of molecular, biochemical, and cell biological approaches, including RT-PCR, microarrays, Westerns, immunocytochemistry and confocal microscopy, will provide a more complete understanding of the signals and pathways that regulate cerebellar differentiation.

Selected References:

Siegel, R.E., 1988.The mRNAs encoding GABAA/benzodiazepine receptor subunits are localized in different cell populations of the bovine cerebellum.Neuron 1, 579-584.

Gambarana, C., C.J. Loria, and R.E. Siegel, 1993.GABAA receptor mRNA expression in the deep cerebellar nuclei of the Purkinje cell degeneration mutant is maintained following the loss of innervating Purkinje neurons. Neuroscience 52, 63-71.

Beattie, C.E. and R.E. Siegel, 1993 Developmental cues modulate GABAA receptor subunit mRNA expression in cultured cerebellar granule neurons. J. Neurosci. 13, 1784-1792.

Behringer, K.A., L.M. Gault, and R.E. Siegel, 1996. Differential regulation of GABAA receptor subunit mRNAs in rat cerebellar granule neurons: importance of environmental cues. J. Neurochem. 66, 1347-1353.

Nadler, L.S., L.T. Raetzman, K.L. Dunkle, N. Mueller, and R.E. Siegel, 1996. GABAA receptor subunit expression and assembly in cultured rat cerebellar granule neurons. Dev. Brain Res. 97, 216-226.

Gault, L.M. and R.E. Siegel, 1997. Expression of the GABAA receptor d subunit mRNA is selectively modulated by depolarization in cultured rat cerebellar granule neurons. J. Neurosci. 17, 2391-2399.

Gault, L.M. and R.E. Siegel, 1998. NMDA receptor stimulation selectively initiates GABAA receptor d subunit mRNA expression in cultured rat cerebellar granule neurons.  J. Neurochem. 70, 1907-1915.

Raetzman, L.T. and R.E. Siegel, 1999. Immature granule neurons from cerebella of different ages exhibit distinct developmental potentials. J. Neurobiol. 38, 559-570.

Rieff, H.I., L.T. Raetzman, D. Paas, H. Yeh, R.E. Siegel, and G. Corfas. 1999. Neuregulin induces neurite outgrowth and GABAA receptor subunit expression in cerebellar granule neurons. J. Neurosci. 19, 10757-10766.

Kumar, M., X. Luo, P. Quirk, and R.E. Siegel, 2001. Antisense suppression of GABAA receptor b subunit levels in cultured cerebellar granule neurons demonstrates their importance in receptor expression. J. Neurochem. 77, 211-219.

Angley, C.,M. Kumar, K.J. Dinsio, A.K. Hall, and R.E. Siegel, 2003. Signaling by BMPs and Smad1 modulates the postnatal differentiation of cerebellar cells. J. Neurosci. 23, 260-268.

Hsieh, Y-H, R.E. Siegel, and T.E. Dick, 2004. Pontine GABAergic pathways: role and plasticity in the hypoxic ventilatory response. Respir. Physiol Neurobiol., 143, 141-153.

Quirk, P.L., S. Rao, B.L. Roth,and R.E. Siegel, 2004. N-linked glycosylation of the murine 5-HT3A receptor is necessary for maximal plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells. J. Neurosci. Res., 76, 498-506.

Xie, F., L.R. Raetzman, and R.E. Siegel, 2004. Neuregulin induces GABAA receptor b2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways. J. Neurochem. 90, 1521-1529.

Xie, F., M. Padival, and R.E. Siegel. 2007. Association of PSD-95 with ErbB4 facilitates neuregulin signaling in cerebellar granule neurons in culture. J. Neurochem, 100, 62-72.

Hsieh, Y-H, T.E. Dick, and R.E. Siegel, 2008. Adaptation to hypobaric hypoxia involves GABAA receptors in the pons.Am J. Physiol. Regul. Integr. Comp. Physiol, 294, R549-57.

Berti-Mattera, L.N., T.S. Kern, R.E. Siegel, I. Nemet, and R. Mitchell, 2008. Sulfasalazine blocks the development of tactile allodynia in diabetic rats. Diabetes, 57, 2801-2808.

Siegel, R.E., 2008. GABA-A receptor alpha 6 subunit. UCSD - Nature Molecule Pages.