Hepatocyte Expression of Serum Response Factor Is Essential for Liver Function, Hepatocyte Proliferation and Survival, and Postnatal Body Growth in Mice

Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Hepatology (Impact Factor: 11.06). 05/2009; 49(5):1645-54. DOI: 10.1002/hep.22834
Source: PubMed


Serum response factor (SRF) is a transcription factor that binds to a CarG box motif within the serum response element of genes that are expressed in response to mitogens. SRF plays essential roles in muscle and nervous system development; however, little is known about the role of SRF during liver growth and function. To examine the function of SRF in the liver, we generated mice in which the Srf gene was specifically disrupted in hepatocytes. The survival of mice lacking hepatic SRF activity was lower than that of control mice; moreover, surviving mutant mice had lower blood glucose and triglyceride levels compared with control mice. In addition, Srf(loxP/loxP)AlfpCre mice were smaller and had severely depressed levels of serum insulin-like growth factor 1 (IGF-1). Srf-deficient livers were also smaller than control livers, and liver cell proliferation and viability were compromised. Gene array analysis of SRF depleted livers revealed a reduction in many messenger RNAs, including those encoding components of the growth hormone/IGF-1 pathway, cyclins, several metabolic regulators, and cytochrome p450 enzymes. Conclusion: SRF is essential for hepatocyte proliferation and survival, liver function, and control of postnatal body growth by regulating hepatocyte gene expression.

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Available from: Ravi Misra, May 06, 2014
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    • "To do so, human and murine liver tissues with and without steatosis were triple stained for the nuclear markers Ki67, HNF4α and DAPI. HNF4α has previously been demonstrated to specifically stain hepatpatocytes in the liver [17]. The overall number of proliferating Ki67 positive cells as a percentage of total number of DAPI positive cells as well as the percentage of co-positive Ki67/HNFα proliferating hepatocytes vs total HNF4a positive hepatocytes were counted and quantified per field. "
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    PLoS ONE 09/2013; 8(9):e73054. DOI:10.1371/journal.pone.0073054 · 3.23 Impact Factor
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    • "In addition to cell differentiation, SRF has been implicated in cell survival of various cell types including hepatocytes [2], thymocytes [3], heart cells [4], and during embryogenesis [5]. In embryonic stem cells lacking SRF apoptosis was strongly upregulated [4]. "
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    Journal of Neuroinflammation 04/2012; 9(1):78. DOI:10.1186/1742-2094-9-78 · 5.41 Impact Factor
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    • "Secondly, SRF emerges as transcriptional regulator of many genes encoding components of insulin or insulin growth factor (IGF) signaling in neurons and non-neuronal cells. These genes include the insulin gene (Sarkar et al., 2011), Igf1 (Charvet et al., 2006; Sun et al., 2009), and, e.g., Ctgf, a protein harboring an IGF binding domain (Stritt et al., 2009). Such SRF-mediated control of insulin/IGF regulation in neurons was also demonstrated to affect neighboring cells, i.e., oligodendrocytes, in a paracrine manner (Stritt et al., 2009). "
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    ABSTRACT: In recent years, the transcription factor serum response factor (SRF) was shown to contribute to various physiological processes linked to neuronal motility. The latter include cell migration, axon guidance, and, e.g., synapse function relying on cytoskeletal dynamics, neurite outgrowth, axonal and dendritic differentiation, growth cone motility, and neurite branching. SRF teams up with myocardin related transcription factors (MRTFs) and ternary complex factors (TCFs) to mediate cellular actin cytoskeletal dynamics and the immediate-early gene (IEG) response, a bona fide indicator of neuronal activation. Herein, I will discuss how SRF and cofactors might modulate physiological processes of neuronal motility. Further, potential mechanisms engaged by neurite growth promoting molecules and axon guidance cues to target SRF's transcriptional machinery in physiological neuronal motility will be presented. Of note, altered cytoskeletal dynamics and rapid initiation of an IEG response are a hallmark of injured neurons in various neurological disorders. Thus, SRF and its MRTF and TCF cofactors might emerge as a novel trio modulating peripheral and central axon regeneration.
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