Klf9 is necessary and sufficient for Purkinje cell survival in organotypic culture

Lebrun, Clément; Avci, Hasan X.; Wehrlé, Rosine; Doulazmi, Mohamed; Jaudon, Fanny; Morel, Marie-Pierre; Rivals, Isabelle; Ema, Masatsugu; Schmidt, Susanne; Sotelo, Constantino; Vodjdani, Guilan; Dusart, Isabelle

doi:10.1016/j.mcn.2012.11.010

Cited by 22 publications

(10 citation statements)

References 57 publications

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“…Cerebellar organotypic cultures were set up from newborn (P0) mice as previously described (Lebrun et al ., 2013). Mice were decapitated, and their brains were dissected out in cold Gey's balanced salt solution (Invitrogen) supplemented with 5 mg/ml glucose.…”

Section: Methodsmentioning

confidence: 99%

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

Jaudon

Raynaud

Wehrlé

et al. 2015

MBoC

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Section: Methodsmentioning

confidence: 99%

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

Jaudon

Raynaud

Wehrlé

et al. 2015

MBoC

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“…Thus, in neuronal cells Klf9 first promotes, then maintains the differentiated state. It is also required for survival of adult-born dentate granule neurons and Purkinje neurons of the cerebellum [15, 16], and it promotes oligodendrocyte differentiation and the expression of myelinating genes [17]. Consistent with these findings, Klf9-null mice show neurological defects, including deficits in fear conditioning and late-stage neurogenesis [6, 16].…”

Section: Introductionmentioning

confidence: 97%

The Krüppel-like factor 9 cistrome in mouse hippocampal neurons reveals predominant transcriptional repression via proximal promoter binding

2017

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BackgroundKrüppel-like factor 9 (Klf9) is a zinc finger transcription factor that functions in neural cell differentiation, but little is known about its genomic targets or mechanism of action in neurons.ResultsWe used the mouse hippocampus-derived neuronal cell line HT22 to identify genes regulated by Klf9, and we validated our findings in mouse hippocampus. We engineered HT22 cells to express a Klf9 transgene under control of the tetracycline repressor, and used RNA sequencing to identify genes modulated by Klf9. We found 217 genes repressed and 21 induced by Klf9. We also engineered HT22 cells to co-express biotin ligase and a Klf9 fusion protein containing an N-terminal biotin ligase recognition peptide. Using chromatin-streptavidin precipitation (ChSP) sequencing we identified 3,514 genomic regions where Klf9 associated. Seventy-five percent of these were within 1 kb of transcription start sites, and Klf9 associated in chromatin with 60% of the repressed genes. We analyzed the promoters of several repressed genes containing Klf9 ChSP peaks using transient transfection reporter assays and found that Klf9 repressed promoter activity, which was abolished after mutation of Sp/Klf-like motifs. Knockdown or knockout of Klf9 in HT22 cells caused dysregulation of Klf9 target genes. Chromatin immunoprecipitation assays showed that Klf9 associated in chromatin from mouse hippocampus with genes identified by ChSP sequencing on HT22 cells, and expression of Klf9 target genes was dysregulated in the hippocampus of neonatal Klf9-null mice. Gene ontology analysis revealed that Klf9 genomic targets include genes involved in cystokeletal remodeling, Wnt signaling and inflammation.ConclusionsWe have identified genomic targets of Klf9 in hippocampal neurons and created a foundation for future studies on how it functions in chromatin, and regulates neuronal morphology and survival across the lifespan.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3640-7) contains supplementary material, which is available to authorized users.

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“…Alternatively, previous studies have shown that Klf3 and Klf5 play a redundant role with Klf4 during cellular reprogramming to reverse the highly differentiated state of a somatic cell back to a pluripotent state (Jiang et al, 2008). This suggests that other KLF family members expressed in the CNS (such as Klf4, Klf7 and Klf9) (Blackmore et al, 2012; Laub et al, 2001a, 2001b; Lebrun et al, 2013; Seo et al, 2012) might play a redundant role with TIEG1 during the development of the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

TGFβ2 regulates hypothalamic Trh expression through the TGFβ inducible early gene-1 (TIEG1) during fetal development

Martínez-Armenta

León-Guerrero

Catalán

et al. 2015

Molecular and Cellular Endocrinology

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The hypothalamus regulates the homeostasis of the organism by controlling hormone secretion from the pituitary. The molecular mechanisms that regulate the differentiation of the hypothalamic thyrotropin-releasing hormone (TRH) phenotype are poorly understood. We have previously shown that Klf10 or TGFβ inducible early gene-1 (TIEG1) is enriched in fetal hypothalamic TRH neurons. Here, we show that expression of TGFβ isoforms (1–3) and both TGFβ receptors (TβRI and II) occurs in the hypothalamus concomitantly with the establishment of TRH neurons during late embryonic development. TGFβ2 induces Trh expression via a TIEG1 dependent mechanism. TIEG1 regulates Trh expression through an evolutionary conserved GC rich sequence on the Trh promoter. Finally, in mice deficient in TIEG1, Trh expression is lower than in wild type animals at embryonic day 17. These results indicate that TGFβ signaling, through the upregulation of TIEG1, plays an important role in the establishment of Trh expression in the embryonic hypothalamus.

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Klf9 is necessary and sufficient for Purkinje cell survival in organotypic culture

Cited by 22 publications

References 57 publications

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

The Krüppel-like factor 9 cistrome in mouse hippocampal neurons reveals predominant transcriptional repression via proximal promoter binding

TGFβ2 regulates hypothalamic Trh expression through the TGFβ inducible early gene-1 (TIEG1) during fetal development

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