scholarly journals Forkhead Transcription Factor FoxM1 Regulates Mitotic Entry and Prevents Spindle Defects in Cerebellar Granule Neuron Precursors

2007 ◽  
Vol 27 (23) ◽  
pp. 8259-8270 ◽  
Author(s):  
Ulrich Schüller ◽  
Qing Zhao ◽  
Susana A. Godinho ◽  
Vivi M. Heine ◽  
René H. Medema ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Target Genes ◽  
Cyclin B1 ◽  
Null Alleles ◽  
Cerebellar Granule Neuron ◽  
Forkhead Transcription Factor ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Granule Neuron Precursors

ABSTRACT The forkhead transcription factor FoxM1 has been reported to regulate, variously, proliferation and/or spindle formation during the G2/M transition of the cell cycle. Here we define specific functions of FoxM1 during brain development by the investigation of FoxM1 loss-of-function mutations in the context of Sonic hedgehog (Shh)-induced neuroproliferation in cerebellar granule neuron precursors (CGNP). We show that FoxM1 is expressed in the cerebellar anlagen as well as in postnatal proliferating CGNP and that it is upregulated in response to activated Shh signaling. To determine the requirements for FoxM1 function, we used transgenic mice carrying conventional null alleles or conditionally targeted alleles in conjunction with specific Cre recombinase expression in CGNP or early neural precursors driven by Math1 or Nestin enhancers. Although the overall cerebellar morphology was grossly normal, we observed that the entry into mitosis was postponed both in vivo and in Shh-treated CGNP cultures. Cell cycle analysis and immunohistochemistry with antibodies against phosphorylated histone H3 indicated a significant delay in the G2/M transition. Consistent with this, FoxM1-deficient CGNP showed decreased levels of the cyclin B1 and Cdc25b proteins. Furthermore, the loss of FoxM1 resulted in spindle defects and centrosome amplification. These findings indicate that the functions of FoxM1 in Shh-induced neuroproliferation are restricted to the regulation of the G2/M transition in CGNP, most probably through transcriptional effects on target genes such as those coding for B-type cyclins.

Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors

2007 ◽  
Vol 67 (6) ◽  
pp. 2676-2684 ◽  
Author(s):  
Frederique Zindy ◽  
Tamar Uziel ◽  
Olivier Ayrault ◽  
Christopher Calabrese ◽  
Marc Valentine ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Alterations ◽  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Granule Neuron Precursors

scholarly journals The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

2018 ◽  
Vol 39 (1) ◽  
pp. 44-62 ◽  
Author(s):  
Xiaoying Chen ◽  
Ayan Chanda ◽  
Yoshiho Ikeuchi ◽  
Xiaoqing Zhang ◽  
Jared V. Goodman ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Transcriptional Regulator ◽  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Granule Neuron Precursors

scholarly journals Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a)

2001 ◽  
Vol 21 (3) ◽  
pp. 952-965 ◽  
Author(s):  
Anne Brunet ◽  
Jongsun Park ◽  
Hien Tran ◽  
Linda S. Hu ◽  
Brian A. Hemmings ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Survival ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Cellular Functions ◽  
Forkhead Transcription Factor ◽  
Pi3k Activation ◽  
Phosphoinositide 3 Kinase

ABSTRACT Serum- and glucocorticoid-inducible kinases (SGKs) form a novel family of serine/threonine kinases that are activated in response to a variety of extracellular stimuli. SGKs are related to Akt (also called PKB), a serine/threonine kinase that plays a crucial role in promoting cell survival. Like Akt, SGKs are activated by the phosphoinositide-3 kinase (PI3K) and translocate to the nucleus upon growth factor stimulation. However the physiological substrates and cellular functions of SGKs remained to be identified. We hypothesized that SGKs regulate cellular functions in concert with Akt by phosphorylating common targets within the nucleus. The best-characterized nuclear substrates of Akt are transcription factors of the Forkhead family. Akt phosphorylates Forkhead transcription factors such as FKHRL1, leading to FKHRL1's exit from the nucleus and the consequent shutoff of FKHRL1 target genes. We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1. However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression.

scholarly journals Activated Notch2 Signaling Inhibits Differentiation of Cerebellar Granule Neuron Precursors by Maintaining Proliferation

Neuron ◽  
2001 ◽  
Vol 31 (4) ◽  
pp. 557-568 ◽  
Author(s):  
David J. Solecki ◽  
XiaoLin Liu ◽  
Toshifumi Tomoda ◽  
Yin Fang ◽  
Mary E. Hatten
Keyword(s):  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Granule Neuron Precursors

scholarly journals A Novel Role of the Mad Family Member Mad3 in Cerebellar Granule Neuron Precursor Proliferation

2007 ◽  
Vol 27 (23) ◽  
pp. 8178-8189 ◽  
Author(s):  
Jun-Soo Yun ◽  
Jennifer M. Rust ◽  
Tatsuto Ishimaru ◽  
Elva Díaz
Keyword(s):  
Dna Binding ◽  
Family Member ◽  
Function Analysis ◽  
Dependent Manner ◽  
Cerebellar Granule Neuron ◽  
Cerebellar Granule ◽  
Granule Neuron ◽  
Shh Pathway ◽  
Cerebellar Tissue ◽  
Granule Neuron Precursors

ABSTRACT During development, Sonic hedgehog (Shh) regulates the proliferation of cerebellar granule neuron precursors (GNPs) in part via expression of Nmyc. We present evidence supporting a novel role for the Mad family member Mad3 in the Shh pathway to regulate Nmyc expression and GNP proliferation. Mad3 mRNA is transiently expressed in GNPs during proliferation. Cultured GNPs express Mad3 in response to Shh stimulation in a cyclopamine-dependent manner. Mad3 is necessary for Shh-dependent GNP proliferation as measured by bromodeoxyuridine incorporation and Nmyc expression. Furthermore, Mad3 overexpression, but not that of other Mad proteins, is sufficient to induce GNP proliferation in the absence of Shh. Structure-function analysis revealed that Max dimerization and recruitment of the mSin3 corepressor are required for Mad3-mediated GNP proliferation. Surprisingly, basic-domain-dependent DNA binding of Mad3 is not required, suggesting that Mad3 interacts with other DNA binding proteins to repress transcription. Interestingly, cerebellar tumors and pretumor cells derived from patched heterozygous mice express high levels of Mad3 compared with adjacent normal cerebellar tissue. Our studies support a novel role for Mad3 in cerebellar GNP proliferation and possibly tumorigenesis, and they challenge the current paradigm that Mad3 should antagonize Nmyc by competition for direct DNA binding via Max dimerization.

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