scholarly journals Promotion of Axon Growth by the Secreted End of a Transcription Factor

Cell Reports ◽  
2019 ◽  
Vol 29 (2) ◽  
pp. 363-377.e5 ◽  
Author(s):  
Ethan P. McCurdy ◽  
Kyung Min Chung ◽  
Carlos R. Benitez-Agosto ◽  
Ulrich Hengst
Keyword(s):  
Transcription Factor ◽  
Axon Growth

scholarly journals Molecular cloning and characterization of a transcription factor for the copia retrotransposon with homology to the BTB-containing lola neurogenic factor.

1997 ◽  
Vol 17 (1) ◽  
pp. 482-494 ◽  
Author(s):  
L Cavarec ◽  
S Jensen ◽  
J F Casella ◽  
S A Cristescu ◽  
T Heidmann
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activation ◽  
Axon Growth ◽  
Expression Vectors ◽  
Recognition Sequence ◽  
Enhancer Sequence ◽  
Cells In Culture ◽  
Copia Retrotransposon ◽  
Gel Shift ◽  
In Cells

By transfection experiments, we previously identified a 72-bp enhancer sequence within the Drosophila copia retrotransposon which is involved in the control of the transcription level of this mobile element in cells in culture. Gel shift assays with nuclear extracts from Drosophila hydei-derived DH-33 cells further demonstrated specific interactions of at least two nuclear factors with this enhancer sequence. Using this sequence as a probe for the screening of an expression cDNA library that we constructed from DH-33 cells RNA, we have isolated a cDNA clone encoding a 110-kDa protein with features common to those of known transcription factors; these include a two-zinc-finger motif at the C terminus, three glutamine-rich domains in the presumptive activation domain of the protein, and an N-terminal domain which shares homology with the Bric-à-brac, Tramtrack, and Broad-Complex BTB boxes. The precise DNA recognition sequence for this transcription factor has been determined by both gel shift assays and footprinting experiments with a recombinant protein made in bacteria. The functionality of the cloned element was demonstrated upon transcriptional activation of copia reporter genes, as well as of a minimal promoter coupled with the identified target DNA sequence, in cotransfection assays in cells in culture with an expression vector for the cloned factor. Southern blot and nucleotide sequence analyses revealed a related gene in Drosophila melanogaster (the lola gene) previously identified by a genetic approach as involved in axon growth and guidance. Transfection assays in cells in culture with lola gene expression vectors and in situ hybridization experiments with lola gene mutants finally provided evidence that the copia retrotransposon is regulated by this neurogenic gene in D.melanogaster, with a repressor effect in the central nervous systems of the embryos.

scholarly journals Neuropilin-1 Is a Direct Target of the Transcription Factor E2F1 during Cerebral Ischemia-Induced Neuronal Death In Vivo

2006 ◽  
Vol 27 (5) ◽  
pp. 1696-1705 ◽  
Author(s):  
Susan X. Jiang ◽  
Melissa Sheldrick ◽  
Angele Desbois ◽  
Jacqueline Slinn ◽  
Sheng T. Hou
Keyword(s):  
Transcription Factor ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Axon Growth ◽  
Receptor Expression ◽  
Luciferase Reporter ◽  
Semaphorin 3A ◽  
Neuropilin 1 ◽  
Direct Target ◽  
Transcription Factor E2f1

ABSTRACT The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1+/+ and E2F1−/− mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1−/− neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1−/− neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.

scholarly journals Examining the relationship between early axon growth and transcription factor expression in the developing cerebral cortex

2012 ◽  
Vol 220 (3) ◽  
pp. 201-211 ◽  
Author(s):  
Tom Lickiss ◽  
Amanda F. P. Cheung ◽  
Charlotte E. Hutchinson ◽  
Jeremy S. H. Taylor ◽  
Zoltán Molnár
Keyword(s):  
Transcription Factor ◽  
Cerebral Cortex ◽  
Axon Growth ◽  
Factor Expression ◽  
Transcription Factor Expression ◽  
The Relationship

scholarly journals KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

2018 ◽  
Author(s):  
Zimei Wang ◽  
Vatsal Mehra ◽  
Matthew.T. Simpson ◽  
Brian Maunze ◽  
Lyndsey Holan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cortical Neurons ◽  
Gene Networks ◽  
Axon Regeneration ◽  
Growth Promotion ◽  
Spinal Injury ◽  
Axon Growth ◽  
Genome Wide ◽  
Two Factors ◽  
Constitutively Active

ABSTRACTMembers of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration in the central nervous system, but the underlying mechanisms are unclear. KLF6 and −7 share nearly identical DNA binding domains and stand out as the only known growth-promoting family members. Here we confirm that similar to KLF7, expression of KLF6 declines during postnatal cortical development and that forced re-expression of KLF6 in corticospinal tract neurons of adult female mice enhances axon regeneration after cervical spinal injury. Unlike KLF7, however, these effects were achieved with wildtype KLF6, as opposed constitutively active mutants, thus simplifying the interpretation of mechanistic studies. To clarify the molecular basis of growth promotion, RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in cortical neurons. Network analysis of these genes revealed sub-networks of downregulated genes that were highly enriched for synaptic functions, and sub-networks of upregulated genes with functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis and transport, and bioenergetics. The promoter regions of KLF6-sensitive genes showed enrichment for the binding sequence of STAT3, a previously identified regeneration-associated gene. Notably, co-expression of constitutively active STAT3 along with KLF6 in cortical neurons produced synergistic increases in neurite length. Finally, genome-wide ATAC-seq footprinting detected frequent co-binding by the two factors in pro-growth gene networks, indicating co-occupancy as an underlying mechanism for the observed synergy. These findings advance understanding of KLF-stimulated axon growth and indicate functional synergy of KLF6 transcriptional effects with those of STAT3.SIGNIFICANCE STATEMENTThe failure of axon regeneration in the CNS limits recovery from damage and disease. These findings show the transcription factor KLF6 to be a potent promoter of axon growth after spinal injury, and more importantly clarify the underlying transcriptional changes. In addition, bioinformatics analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting confirmed frequent co-occupancy. Co-expression of the two factors yielded synergistic elevation of neurite growth in primary neurons. These data point the way toward novel transcriptional interventions to promote CNS regeneration.

scholarly journals Phenotypic Screening Following Transcriptomic Deconvolution to Identify Transcription Factors Mediating Axon Growth Induced by a Kinase Inhibitor

2021 ◽  
pp. 247255522110262
Author(s):  
Jeffrey A. Lowell ◽  
Nicholas O’Neill ◽  
Matt C. Danzi ◽  
Hassan Al-Ali ◽  
John L. Bixby ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Growth Regulation ◽  
Kinase Inhibitor ◽  
Axon Growth ◽  
Transcriptional Regulators ◽  
Phenotypic Screening

After injury to the central nervous system (CNS), both neuron-intrinsic limitations on regenerative responses and inhibitory factors in the injured CNS environment restrict regenerative axon growth. Instances of successful axon regrowth offer opportunities to identify features that differentiate these situations from that of the normal adult CNS. One such opportunity is provided by the kinase inhibitor RO48, which dramatically enhances neurite outgrowth of neurons in vitro and substantially increased contralateral sprouting of corticospinal tract neurons when infused intraventricularly following unilateral pyramidotomy. The authors present here a transcriptomic deconvolution of RO48-associated axon growth, with the goal of identifying transcriptional regulators associated with axon growth in the CNS. Through the use of RNA sequencing (RNA-seq) and transcription factor binding site enrichment analysis, the authors identified a list of transcription factors putatively driving differential gene expression during RO48-induced neurite outgrowth of rat hippocampal neurons in vitro. The 82 transcription factor motifs identified in this way included some with known association to axon growth regulation, such as Jun, Klf4, Myc, Atf4, Stat3, and Nfatc2, and many with no known association to axon growth. A phenotypic loss-of-function screen was carried out to evaluate these transcription factors for their roles in neurite outgrowth; this screen identified several potential outgrowth regulators. Subsequent validation suggests that the Forkhead box (Fox) family transcription factor Foxp2 restricts neurite outgrowth, while FoxO subfamily members Foxo1 and Foxo3a promote neurite outgrowth. The authors’ combined transcriptomic-phenotypic screening strategy therefore allowed identification of novel transcriptional regulators of neurite outgrowth downstream of a multitarget kinase inhibitor.

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