Transcriptional regulation of myotube fate specification and intrafusal muscle fiber morphogenesis

Albert, Yvonne B; Whitehead, Jennifer L.; Eldredge, Laurie C.; Carter, John; Gao, Xin; Tourtellotte, Warren G.

doi:10.1083/jcb.200501156

Cited by 34 publications

(59 citation statements)

References 25 publications

(58 reference statements)

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“…In support of this possibility, similar promoter analysis on the set of genes induced by overexpression of Egr3 in myotubes also did not yield significant enrichment of Egr-binding sites (Ref. 26 and data not shown), yet several directly regulated target genes have been identified and well-characterized from the array data set (26,27). Alternatively, this may indicate that a large number of down-regulated genes are indirectly regulated by Egr1 and/or Egr3.…”

Section: Discussionmentioning

confidence: 75%

Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival

Carter

Lefebvre

Wiest

et al. 2007

The Journal of Immunology

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The early growth response (Egr) family of transcriptional regulators consists of four proteins that share highly conserved DNAbinding domains. In many cell types, they are coexpressed and appear to have cooperative roles in regulating gene expression during growth and differentiation. Three Egr proteins, Egr1, Egr2, and Egr3, are induced during thymocyte differentiation in response to pre-TCR signaling, suggesting they may be critical for some aspects of pre-TCR-mediated differentiation. Indeed, enforced expression of Egr proteins in developing thymocytes can recapitulate some aspects of pre-TCR signaling, but the mechanisms by which they contribute to ␤-selection are still poorly understood. Egr3 stimulates proliferation of ␤-selected thymocytes, and Egr3-deficient mice have hypocellular thymuses, defects in proliferation, and impaired progression from double-negative 3 to double-negative 4. Surprisingly, Egr1-deficient mice exhibit normal ␤-selection, indicating that the functions of Egr1 during ␤-selection are likely compensated by other Egr proteins. In this study, we show that mice lacking both Egr1 and Egr3 exhibit a more severe thymic atrophy and impairment of thymocyte differentiation than mice lacking either Egr1 or Egr3. This is due to a proliferation defect and cell-autonomous increase in apoptosis, indicating that Egr1 and Egr3 cooperate to promote thymocyte survival. Microarray analysis of deregulated gene expression in immature thymocytes lacking both Egr1 and Egr3 revealed a previously unknown role for Egr proteins in the maintenance of cellular metabolism, providing new insight into the function of these molecules during T cell development. The Journal of Immunology, 2007, 178: 6796 -6805.T cell development in the thymus progresses through welldefined stages characterized by the expression of the CD4 and CD8 cell surface markers. The earliest T cell precursors express neither CD4 nor CD8 (double-negative (DN) 3 thymocytes), which progress through a series of maturational steps to form double-positive (DP) thymocytes that express both CD4 and CD8, and then finally to mature single-positive (SP) thymocytes that express either CD4 or CD8. DN thymocytes can be further subdivided into several substages of maturation on the basis of CD25 and CD44 expression, namely DN1 (CD44 ϩ and CD25 Ϫ ), DN2 (CD44 ϩ and CD25 ϩ ), DN3 (CD44 Ϫ and CD25 ϩ ), and DN4 (CD44 Ϫ and CD25 Ϫ ) thymocytes (1). As part of this complex maturational process, rearrangement of the TCR␤ gene occurs at the DN3 stage during which cells express the successfully rearranged TCR␤ gene along with the pre-TCR␣ (pT␣) chain to form the functional pre-TCR receptor complex. Signaling through the pre-TCR receptor involves a variety of cellular responses, including robust proliferation, enhanced cell survival, down-regulation of the Rag1 and Rag2 recombinase genes, reduced CD25 expression, decreased pT␣ expression, induction of the TCR␣ chain, and allelic exclusion of the nonrearranged TCR␤ locus (2). Differentiation through DN3 to DN4 is known a...

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Section: Discussionmentioning

confidence: 75%

Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival

Carter

Lefebvre

Wiest

et al. 2007

The Journal of Immunology

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“…The microinjections of the transgene were performed by the Northwestern Transgenic and Targeted Mutagenesis Core Facility, as described previously (52). Potential founder mice (which grew from the injected zygotes) were screened for insertion of the transgene by PCR analysis after DNA was obtained from their tail tip.…”

Section: Methodsmentioning

confidence: 99%

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

734

559

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Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.

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“…4). In addition, parvalbumin (Pv) immunohistochemistry was used as a wellestablished marker of proprioceptive sensory innervation to skeletal muscle stretch receptors (Albert et al, 2005;Tourtellotte et al, 2001), which was highly significantly reduced to 4.8% in Wnt1-cKO skeletal muscle compared with Wnt1-Ctl mice (n=2 mice and over 30 tissue sections analyzed per genotype, P<0.0001, Student's t-test) (Fig. 4).…”

Section: Generating Viable Elp1 Conditional Knockout Micementioning

confidence: 99%

“…Reverse transcriptase (RT)-PCR and qPCR were performed as previously (Albert et al, 2005;Quach et al, 2013) and are outlined in detail in supplementary methods (see supplementary material).…”

Section: Gene Expression Analysismentioning

confidence: 99%

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Jackson¹,

Gruner

Qin

et al. 2014

Development

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Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and target tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal target tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation.

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Transcriptional regulation of myotube fate specification and intrafusal muscle fiber morphogenesis

Cited by 34 publications

References 25 publications

Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival

Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

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