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