Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element.
DARPP-32 (dopamine and adenosine 3', 5'-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), a known inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, overexpression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominant-negative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation.
Keilani, Serene; Chandwani, Samira; Dolios, Georgia; Bogush, Alexey; Beck, Heike; Hatzopoulos, Antonis K; Rao, Gadiparthi N; Thomas, Elizabeth A; Wang, Rong; and Ehrlich, Michelle E, "Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element." (2012). Farber Institute for Neuroscience Faculty Papers. Paper 16.
This article has been peer reviewed and is published in Journal of Neuroscience.
Volume 32, Issue 20, 16 May 2012, Pages 6808-6818.
The published version is available at DOI: 10.1523/JNEUROSCI.5448-11.2012. © 2012 the authors.