Transcription factors play essential roles in the processes of neuronal cell fate determination and expression of the mature neuronal phenotype that are necessary for normal development and function of the brain. My laboratory is investigating expression of the cyclin-dependent kinase 5 (cdk5) activator p35 as a model to understand the molecular mechanisms of cell type-specific transcription in neurons. The heterodimeric cdk5/p35 kinase plays a role in many neuronal processes ranging from neuronal migration and axon guidance to synaptic plasticity and drug addiction. Furthermore, improper cdk5 activity, caused by association with a proteolytic fragment of p35, has been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis. A repeated GC box element in the p35 promoter is necessary and sufficient for neuron-specific gene expression. The studies described in this proposal are designed to test the hypothesis that the mechanisms that regulate the levels and activity of the GC box-binding transcription factors Sp1, Sp3 and Sp4 during neurogenesis contribute to neuronal-specific expression of p35.
The specific aims of this research are to (1) determine which Sp transcription factors are important for GC box-dependent expression of p35 in neurons, (2) determine the mechanisms that regulate Sp transcription factor stability during neurogenesis, and (3) determine how SUMO-1 mediated repression of Sp3 is relieved in post-mitotic neurons. In addition to advancing our specific knowledge of the transcriptional mechanisms that regulate activity of the cdk5/p35 kinase, these studies will provide a paradigm for understanding how cell type-specific regulation of transcription factor levels and activity controls neuronal specific expression of many genes whose expression depends on GC box promoter elements. Since disturbances of the finely tuned transcriptional program in neurons are associated with developmental abnormalities and disease, it is imperative to increase our understanding of the molecular mechanisms that underlie cell type-specific gene expression in neurons.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043364-03
Application #
6889283
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Henken, Deborah B
Project Start
2003-07-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$381,375
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Pinacho, Raquel; Saia, Gregory; Fusté, Montserrat et al. (2015) Phosphorylation of transcription factor specificity protein 4 is increased in peripheral blood mononuclear cells of first-episode psychosis. PLoS One 10:e0125115
Pinacho, Raquel; Saia, Gregory; Meana, J Javier et al. (2015) Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects. Eur Neuropsychopharmacol 25:1650-1660
Sun, Xinxin; Pinacho, Raquel; Saia, Gregory et al. (2015) Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning. Dev Neurobiol 75:93-108
Saia, Gregory; Lalonde, Jasmin; Sun, Xinxin et al. (2014) Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. J Neurochem 129:743-52
Lalonde, Jasmin; Saia, Gregory; Gill, Grace (2014) Store-operated calcium entry promotes the degradation of the transcription factor Sp4 in resting neurons. Sci Signal 7:ra51
Pinacho, Raquel; Villalmanzo, Nuria; Lalonde, Jasmin et al. (2011) The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disord 13:474-85
Valin, Alvaro; Cook, Julie D; Ross, Sarah et al. (2009) Sp1 and Sp3 regulate transcription of the cyclin-dependent kinase 5 regulatory subunit 2 (p39) promoter in neuronal cells. Biochim Biophys Acta 1789:204-11
Ramos, Belén; Valín, Alvaro; Sun, Xinxin et al. (2009) Sp4-dependent repression of neurotrophin-3 limits dendritic branching. Mol Cell Neurosci 42:152-9
Ramos, Belen; Gaudilliere, Brice; Bonni, Azad et al. (2007) Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation. Proc Natl Acad Sci U S A 104:9882-7