Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression

Stritt, Christine; Stern, Sina; Harting, Kai; Manke, Thomas; Sinske, Daniela; Schwarz, Heinz; Vingron, Martin; Nordheim, Alfred; Knöll, Bernd

doi:10.1038/nn.2280

Cited by 98 publications

(95 citation statements)

References 49 publications

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“…In comparison, the analysis of the neuronal regulon of other PRTFs has received less attention. The few available studies exploring SRF-dependent (Etkin et al, 2006;Stritt et al, 2009;Parkitna et al, 2010) and FOS-dependent (Wu et al, 2004;Paletzki et al, 2008) neuronal gene expression show disparate results and limited overlap, likely because of the technical reasons stated above. A remarkable difference between our screen and those previous studies is the possibility to quantitatively compare the changes triggered by the expression of each one of these PRTFs.…”

Section: Discussionmentioning

confidence: 99%

cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression

Benito¹,

Valor²,

Jiménez-Minchan³

et al. 2011

J. Neurosci.

106

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Long-lasting forms of neuronal plasticity require de novo gene expression, but relatively little is known about the events that occur genome-wide in response to activity in a neuronal network. Here, we unveil the gene expression programs initiated in mouse hippocampal neurons in response to different stimuli and explore the contribution of four prominent plasticity-related transcription factors (CREB, SRF, EGR1, and FOS) to these programs. Our study provides a comprehensive view of the intricate genetic networks and interactions elicited by neuronal stimulation identifying hundreds of novel downstream targets, including novel stimulus-associated miRNAs and candidate genes that may be differentially regulated at the exon/promoter level. Our analyses indicate that these four transcription factors impinge on similar biological processes through primarily non-overlapping gene-expression programs. Meta-analysis of the datasets generated in our study and comparison with publicly available transcriptomics data revealed the individual and collective contribution of these transcription factors to different activity-driven genetic programs. In addition, both gain-and loss-of-function experiments support a pivotal role for CREB in membrane-to-nucleus signal transduction in neurons. Our data provide a novel resource for researchers wanting to explore the genetic pathways associated with activity-regulated neuronal functions.

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Section: Discussionmentioning

confidence: 99%

cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression

Benito¹,

Valor²,

Jiménez-Minchan³

et al. 2011

J. Neurosci.

106

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“…77 Microarray analysis of SRF-null hippocampi showed reduced expression of a large number of oligodendrocyte-associated genes, including those essential for myelination of neurons. 78 Further analysis showed a non-cell-autonomous increase in oligodendrocyte precursors and reduced differentiated oligodendrocytes in SRF mutants, with reductions in various myelin-related genes. 78 Thus loss of neuronal SRF has severe consequences for the normal development of at least one glial cell type.…”

Section: Srf and Nervous System Disease Central Nervous Systemmentioning

confidence: 99%

“…78 Further analysis showed a non-cell-autonomous increase in oligodendrocyte precursors and reduced differentiated oligodendrocytes in SRF mutants, with reductions in various myelin-related genes. 78 Thus loss of neuronal SRF has severe consequences for the normal development of at least one glial cell type. Recently, loss of SRF in the CNS of perinatal pups resulted in disorganized layering of both hippocampal and cortical neurons with defective dendritic branching and spine formation.…”

Section: Srf and Nervous System Disease Central Nervous Systemmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

119

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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“…SRF might affect these parameters by directly transcriptionally regulating genes encoding, for example, for the fusion or fission machinery (1). All genes annotated for mitochondrial function were screened for SRF binding sites (CArG boxes) in their promoter regions (21). SRF was not predicted to have a strong affinity for any of the known fusion or fission.…”

Section: Srf Is Not a Major Transcriptional Regulator Of Mitochondriamentioning

confidence: 99%

“…These SRF-deficient mice die at 3 wk of age. At this time point, no overall axonal loss but severe demyelination of axons is observed (21). Because mitochondrial dysfunction and axonal demyelination are connected (22), we investigated mitochondrial morphology and function in SRF-deficient mice.…”

mentioning

confidence: 99%

Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

Beck

Flynn

Lindenberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.

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Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression

Cited by 98 publications

References 49 publications

cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression

cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression

Role of serum response factor in the pathogenesis of disease

Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

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