The ontogeny of Krox-20 expression in brainstem and cerebellar neurons

De, Shampa; Shuler, Charles F.; Turman, Jack E.

doi:10.1016/s0891-0618(03)00011-5

Cited by 11 publications

(11 citation statements)

References 45 publications

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“…Our results demonstrate that, contrary to our hypothesis, the mutation impacts the final number of Me5 neurons, altering the apoptotic period associated with Me5 neuron development. Our results extend our previous findings demonstrating that Me5 neurons express Krox-20 as early as E17.0 in the mouse and throughout the entire postnatal period [De et al, 2003]. This suggests that Krox-20 expression is critical for Me5 development and maintenance in mammals.…”

Section: Introductionsupporting

confidence: 90%

“…The proportion of Me5 neurons not present in the Krox-20 null mutant by P0 is approximately equivalent to the fraction of Me5 neurons that express Krox-20 at that age during normal development [De et al, 2003]. This suggests that there is some other protein that is serving an analogous role to Krox-20 in the remaining Me5 neurons.…”

Section: The Reduction Of the Me5 Nucleusmentioning

confidence: 99%

“…Me5 neurons also vary in expression of different genes, such as cholecystokinin, peptide 19, parvalbumin, calbindin and osteocalcin [see review by Lazarov, 2002]. The variability among Me5 neurons in expression of Krox-20 protein [De et al, 2003] and susceptibility to the Krox-20 null mutation also raises questions as to what regulates Krox-20 expression in this nucleus and what mediates proliferation and apoptosis in these cells.…”

Section: The Reduction Of the Me5 Nucleusmentioning

confidence: 99%

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Mesencephalic Trigeminal Nucleus Development Is Dependent on Krox-20 Expression

Nguyen²,

Shuler³

et al. 2005

Dev Neurosci

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Krox-20, a C₂H₂-type zinc-finger transcription factor, plays an important role in rhombomere development. This study reveals that the Krox-20 null mutation impacts the development of mesencephalic trigeminal (Me5) neurons, a cell group traditionally thought to emerge from the mesencephalon. Based on cell counting studies, we show that Krox-20 null mutants have twice as many Me5 neurons relative to wildtypes at E15, but by birth have half the number of Me5 cells as wildtypes. TUNEL studies reveal a period of increased apoptosis from E17-P0 in mutants. The mutation does not result in differences in Me5 cell size, morphology, gene expression or peripheral projection patterns between genotypes, as demonstrated by retrograde tracing and Brn3a immunohistochemistry. The data suggest that Krox-20 regulates the period and extent of Me5 apoptosis, impacting the final number of Me5 neurons. The loss of Me5 in Krox-20^–/– mice may highlight species-specific differences in the origin of these cells.

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Section: Introductionsupporting

confidence: 90%

Section: The Reduction Of the Me5 Nucleusmentioning

confidence: 99%

Section: The Reduction Of the Me5 Nucleusmentioning

confidence: 99%

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Mesencephalic Trigeminal Nucleus Development Is Dependent on Krox-20 Expression

Nguyen²,

Shuler³

et al. 2005

Dev Neurosci

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“…The skeletal phenotype and the expression pattern of Egr2/Krox20 are consistent with a role for this transcription factor in terminally differentiating osteoblasts and in late hypertrophic chondrocytes acquiring an osteoblast-like phenotype (52). OC is a late differentiation marker in both of these cell types (13,53), and, interestingly, OC was also demonstrated in dorsal root ganglia and trigeminal neurons (54), cells that express Egr2/Krox20 (55).…”

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confidence: 93%

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer

Leclerc¹,

Noh²,

Khokhar³

et al. 2005

Arthritis & Rheumatism

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Objective. Glucocorticoids are widely used for the management of rheumatoid arthritis. Osteoporosis is a major side effect of glucocorticoid therapy and is attributable to inhibition of bone formation. We developed an osteoblast culture system in which glucocorticoids strongly inhibit development of the osteoblast phenotype, including expression of the bone-specific osteocalcin (OC) gene. Using this gene as a model, the goal of this study was to discover glucocorticoid-sensitive transcriptional mechanisms in osteoblasts.Methods. Dexamethasone (DEX; 1 M) was administered to murine MC3T3-E1 osteoblastic cultures under conditions that inhibit mineralized extracellular matrix formation and OC messenger RNA levels by >10-fold. Because standard (short-term) transient transfection assays with OC promoter-reporter constructs did not recapitulate the strong DEX-mediated repression, mapping of OC negative glucocorticoid response elements (GREs) was performed initially by stable transfection and then with long-term transient transfection assays. Transcription factor binding to the OC negative GRE was studied by electrophoretic mobility shift assays.Results. Several-fold repression of OC-luciferase constructs was recapitulated in stable and long-term transient transfection assays, in which the transfected cells were allowed to progress to a sufficiently advanced developmental stage. Analysis of a 5 promoter deletion series mapped an OC negative GRE to a 15-bp G/C-rich motif (؊161/؊147) located just upstream of the binding site for the osteoblast master transcription factor Runx2. Oligonucleotides encompassing this element and MC3T3-E1 cell extracts formed a protein-DNA complex that contained an Egr/Krox family member(s). Complex formation was competed by either an oligonucleotide containing 2 consensus Egr motifs or by anti-Egr2/Krox20 antibodies. Three copies of this Kroxbinding element conferred 20-fold transcriptional activation on the 147-bp basal OC promoter in osteoblasts, and the enhancer activity was inhibited by DEX. Enhancer activity was not observed in 10T1/2 fibroblasts unless these cells were cotransfected with Runx2.Conclusion. An Egr2/Krox20-binding site located immediately upstream of the Runx2 site of the mouse OC promoter was identified as an enhancer in osteoblasts, whose activity is repressed by glucocorticoids. Sequence similarity suggests that such a mechanism is likely operative in both murine and human cells. Because glucocorticoids inhibit Egr2/Krox20 expression in osteoblasts, and because trabecular bone formation is arrested in Egr2/Krox20-knockout mice, the inhibition of Egr2/Krox20 activity likely contributes to glucocorticoid-induced osteoporosis.Since the 1950 Nobel laureates E. Kendall, T. Reichstein, and P. Hench introduced glucocorticoids for the treatment of rheumatoid arthritis, these drugs have been widely used for the treatment of autoimmune and inflammatory diseases. The enthusiasm with which glucocorticoids were initially accepted was quickly dampened upon realization of their deleter...

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“…We found that, similar to the immediate early gene egr-1 (De et al, 2003) but unlike its stimulation-dependent expression in the inner ear (Ruan et al, 2007), c-Jun is present in most of the auditory brainstem in normal brains without specific stimulation (Fig. 10).…”

Section: Molecules Upstream Of C-fos Expressionmentioning

confidence: 79%