Serum Response Factor Is Required for Cortical Axon Growth But Is Dispensable for Neurogenesis and Neocortical Lamination

Lu, Paul; Ramanan, Narendrakumar

doi:10.1523/jneurosci.3015-11.2011

Cited by 28 publications

(24 citation statements)

References 53 publications

(75 reference statements)

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“…Our recent findings revealed that Srf-Nestin-cKO mice did not exhibit any deficits in neurogenesis or increased apoptosis during development (Lu and Ramanan, 2011). However, there was an increase in proliferative precursor cells in the subventricular zone in Srf-Nestin-cKO mice (Lu and Ramanan, 2011), which is possibly a result of impairment in glial lineage commitment.…”

Section: Resultsmentioning

confidence: 96%

“…Within the CNS, SRF regulates axon growth, tangential neuronal migration, activitydependent gene expression, synaptic plasticity, and learning and memory (Ramanan et al, 2005;Etkin et al, 2006;Knöll et al, 2006;Stern et al, 2009;Johnson et al, 2011;Lu and Ramanan, 2011). Here, we report a previously unidentified role for SRF in astrocyte and oligodendrocyte differentiation in the brain.…”

Section: Introductionmentioning

confidence: 79%

“…To address this, we conditionally deleted SRF within NPCs using a Nestin-Cre transgenic mouse line (Srf-NestincKO) (Lu and Ramanan, 2011). The Srf-Nestin-cKO mice died neonatally and did not exhibit any defects in cell survival, neurogenesis, or neuronal subtype specification (Lu and Ramanan, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…The Srf-Nestin-cKO and Srf-NEX-cKO were generated as described previously (Lu and Ramanan, 2011) using a Nestin-Cre transgenic mouse line (Tronche et al, 1999) and a NEX-Cre line (Goebbels et al, 2006). The Srf f/ϩ ;NesCre double-heterozygous mice did not exhibit any discernible phenotype.…”

Section: Animals Srfmentioning

confidence: 99%

“…Biotinylated anti-rabbit and anti-mouse secondary antibodies (1:500; Vector Laboratories) were used along with ABC-Elite or VIP staining kits (Vector Laboratories). Cell count and statistical analyses were performed as described previously (Lu and Ramanan, 2011).…”

Section: Animals Srfmentioning

confidence: 99%

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A Critical Cell-Intrinsic Role for Serum Response Factor in Glial Specification in the CNS

Lu¹,

Ramanan²

2012

Journal of Neuroscience

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Astrocytes and oligodendrocytes play crucial roles in nearly every facet of nervous system development and function, including neuronal migration, synaptogenesis, synaptic plasticity, and myelination. Previous studies have widely characterized the signaling pathways important for astrocyte differentiation and unveiled a number of transcription factors that guide oligodendrocyte differentiation in the CNS. However, the identities of the transcription factors critical for astrocyte specification in the brain remain unknown. Here we show that deletion of the stimulus-dependent transcription factor, serum response factor (SRF), in neural precursor cells (NPCs) (Srf-NestincKO) results in nearly 60% loss in astrocytes and 50% loss in oligodendrocyte precursors at birth. Cultured SRF-deficient NPCs exhibited normal growth rate and capacity to self-renew. However, SRF-deficient NPCs generated fewer astrocytes and oligodendrocytes in response to several lineage-specific differentiation factors. These deficits in glial differentiation were rescued by ectopic expression of wild-type SRF in SRF-deficient NPCs. Interestingly, ectopic expression of a constitutively active SRF (SRF-VP16) in NPCs augmented astrocyte differentiation in the presence of pro-astrocytic factors. However, SRF-VP16 expression in NPCs had an inhibitory effect on oligodendrocyte differentiation. In contrast, mice carrying conditional deletion of SRF in developing forebrain neurons (Srf-NEX-cKO) did not exhibit any deficits in astrocytes in the brain. Together, our observations suggest that SRF plays a critical cell-autonomous role in NPCs to regulate astrocyte and oligodendrocyte specification in vivo and in vitro.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Animals Srfmentioning

confidence: 99%

Section: Animals Srfmentioning

confidence: 99%

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A Critical Cell-Intrinsic Role for Serum Response Factor in Glial Specification in the CNS

Lu¹,

Ramanan²

2012

Journal of Neuroscience

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RREB1–MKL2 fusion in biphenotypic “oropharyngeal” sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?

Siegfried

Romary

Escudié

et al. 2018

Genes Chromosomes & Cancer

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An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.

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Neuronal expression of the transcription factor serum response factor modulates myelination in a mouse multiple sclerosis model

Anastasiadou

Liebenehm

Sinske

et al. 2015

Glia

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In multiple sclerosis (MS), neurons in addition to inflammatory cells are now considered to mediate disease origin and progression. So far, molecular and cellular mechanisms of neuronal MS contributions are poorly understood. Herein we analyzed whether neuron-restricted signaling by the neuroprotective transcription factor serum response factor (SRF) modulates de- and remyelination in a rodent MS model. In the mouse cuprizone model, neuron- (Srf (flox/flox;CaMKCreERT2)) but not glia-specific (Srf (flox/flox;PlpCreERT2)) SRF depletion impaired demyelination suggesting impaired debris clearance by astrocytes and microglia. This supports an important role of SRF expression in neurons but not oligodendrocytes in de- and remyelination. During remyelination, NG2- and OLIG2-positive cells of the oligodendrocyte lineage as well as de novo mRNA synthesis of myelin genes were also reduced in neuron-specific Srf mutants. Using the stripe assay, we demonstrate that cortices of cuprizone-fed wild-type mice elicited astrocyte and microglia activation whereas this was abrogated in cuprizone-fed neuron-specific Srf mutants. We identified CCL chemokines (e.g. CCL2) as neuron-derived SRF-regulated paracrine signals rescuing immune cell activation upon neuronal SRF deletion. In summary, we uncovered important roles of neurons and neuronally expressed SRF in MS associated de- and remyelination.

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Serum Response Factor Is Required for Cortical Axon Growth But Is Dispensable for Neurogenesis and Neocortical Lamination

Cited by 28 publications

References 53 publications

A Critical Cell-Intrinsic Role for Serum Response Factor in Glial Specification in the CNS

A Critical Cell-Intrinsic Role for Serum Response Factor in Glial Specification in the CNS

RREB1–MKL2 fusion in biphenotypic “oropharyngeal” sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?

Neuronal expression of the transcription factor serum response factor modulates myelination in a mouse multiple sclerosis model

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