Targeting of the ETS Factor Gabp<i>α</i> Disrupts Neuromuscular Junction Synaptic Function

O'leary, Debra; Noakes, Peter G.; Lavidis, Nickolas A.; Kola, Ismail; Hertzog, Paul J.; Ristevski, Sika

doi:10.1128/mcb.00659-06

Cited by 28 publications

(24 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A caveat noted by Dong et al was that gene targeting did not completely eliminate Shp2 expression in muscles. Indeed it can be difficult to be sure of complete inactivation of any gene in multinucleated muscle fibres (Jaworski et al, 2007;O'Leary et al, 2007). Expression of the Cre recombinase gene was often insufficient to completely excise loxP-targeted genes, such as Shp2, ErbB2 and ErbB4 in multinucleated muscle cells (Dong et al, 2006;Escher et al, 2005;Jaworski and Burden, 2006;Leu et al, 2003), and studies that target the inactivation of genes in specific cells types (such as motor nerve and muscle) do not address acute action and/or actions of neuregulin-1 at later stages of NMJ development.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Ngo

Cole

Sunn

et al. 2012

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

SummaryAt neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signalling through the muscle-specific kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act through muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signalling can modulate n-agrin-induced AChR clustering independently of its effects on transcription.Here we report that neuregulin-1 increased the size of developing AChR clusters when injected into muscles of embryonic mice. We investigated this phenomenon using cultured myotubes, and found that in the ongoing presence of n-agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. This potentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence might function as a second-order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signalling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Ngo

Cole

Sunn

et al. 2012

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…The GABP␣/␤ complex has been shown to have versatile roles in regulating basic cellular functions and tissue-specific functions (9,26,31). Gene-targeting studies of the DNA binding GABP␣ subunit have revealed its critical roles during embryogenesis (25), during the reentry of the cell cycle (41), and in synaptic function at the neuromuscular junction (22,24). In the immune system, we and others showed that GABP critically regulates IL-7R␣ expression (5,38).…”

Section: Vol 28 2008 Gabp␤1l Is Dispensable For Lymphocyte Developmmentioning

confidence: 99%

“…Recent studies revealed that GABP␣ can recruit the histone acetyltransferase p300 to the acetylcholine receptor ε subunit promoter for its activation in subsynaptic nuclei (24). However, contradictory results on the effect of disrupting Gabpa alleles on the formation and function of neuromuscular junction were recently reported (16,22). In the immune system, GABP has been reported to increase transcription from the interleukin-2 (IL-2) enhancer (1) and the Fas promoter (19) in T cells.…”

mentioning

confidence: 99%

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Xue¹,

Jing²,

Bollenbacher-Reilley

et al. 2008

Molecular and Cellular Biology

View full text Add to dashboard Cite

GA binding protein (GABP) is a ubiquitously expressed Ets family transcription factor that consists of two subunits, GABP␣ and GABP␤. GABP␣ binds to DNA, and GABP␤ heterodimerizes with GABP␣ and possesses the ability to transactivate target genes. Our previous studies using GABP␣-deficient mice revealed that GABP␣ is required for the development of both T and B cells. Two splice variants of GABP␤ are generated from the Gabpb1 locus and differ in their carboxy-terminal lengths and sequences. The longer isoform (GABP␤1L) can homodimerize and thus form ␣ 2 ␤ 2 tetramers depending on the gene context, whereas the shorter isoform (GABP␤1S) cannot. In this study, we generated mice that are deficient in GABP␤1L but that retain the expression of GABP␤1S. Surprisingly, GABP␤1L ؊/؊ mice had normal T-and B-cell development, and mature T and B cells showed normal responses to various stimuli. In contrast, targeting both GABP␤1L and GABP␤1S resulted in early embryonic lethality. Because of its incapability of forming homodimers, GABP␤1S has been suspected to have a dominant negative role in regulating GABP target genes. Our findings argue against such a possibility and rather suggest that GABP␤1S has a critical role in maintaining the transcriptional activity of the GABP␣/␤ complex.Ets family transcription factors have diverse functions in development, differentiation, apoptosis, and oncogenesis (15, 31). More than 30 Ets factors have been described, and all of them contain a conserved DNA binding Ets domain of approximately 85 amino acids in length. The Ets domain assumes a winged helix-loop-helix configuration and binds preferentially to a purine-rich consensus DNA sequence containing GGAA/T. GA binding protein (GABP) is the only Ets factor that functions as obligate multimeric proteins and consists of two unrelated subunits, GABP␣ and GABP␤ (26). GABP␣ harbors the Ets domain close to its C terminus and is thus responsible for DNA binding. GABP␤ cannot bind DNA but has transactivation activities. The interaction of these two subunits is mediated by the C terminus of GABP␣, including the ETS domain, and the ankyrin repeats at the N terminus of GABP␤.GABP was originally identified in studies of viral gene transcription (36, 37), but it is now known to regulate genes that control many basic cellular functions such as cellular respiration in mitochondria (30), protein components of ribosomes (10), and cell cycle progression (14, 32). A recent study using GABP␣-deficient fibroblasts demonstrated that GABP␣ is required for reentry into the cell cycle by regulating the expression of genes that are required for DNA synthesis (such as thymidylate synthase) and the degradation of cyclin-dependent kinase inhibitors (such as S-phase kinase-associated protein) (41). The observation that the inactivation of both Gabpa alleles resulted in death prior to implantation highlights its essential roles for early embryogenesis (25). In addition to these basic cellular functions, GABP regulates tissue-specific target genes, such as those encodi...

show abstract

“…7 Genetic inactivation of individual Ets factors in the mouse has revealed unique, essential Ets functions in diverse biological processes, including hematopoiesis, immune function, lymph/angiogenesis, neurogenesis/neuromuscular function, spermatogenesis, early embryonic patterning, and development of extraembryonic tissues. 1,[7][8][9][10][11][12][13][14][15][16] Interestingly, such studies have been remarkable for the absence of phenotypes in a number of tissues with Ets expression, especially those comprising solid organs. The relative paucity of Ets phenotypes in such tissues appears to be attributable to the multiplicity of expression of different Ets factors in the same cell, combined with the ability of co-expressed Ets factors to compensate for each other's function.…”

mentioning

confidence: 99%

Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine

Jedlicka

Sui

Sussel

et al. 2009

The American Journal of Pathology

View full text Add to dashboard Cite

Members of the Ets transcription factor family are widely expressed in both the developing and mature mammalian intestine, but their biological functions remain primarily uncharacterized. We used a dominant repressor transgene approach to probe the function of epithelial Ets factors in the homeostasis of the crypt-villus unit, the functional unit of the small intestine. We show that targeted expression in small intestinal epithelium of a fusion protein composed of the Engrailed repressor domain and the Erm DNAbinding domain (En/Erm) results in marked disruption of normal crypt-villus homeostasis, including a cell-autonomous disturbance of epithelial maturation, increased epithelial transit, severe villus dysmorphogenesis, and crypt dysmorphogenesis. The epithelial maturation disturbance is independent of the regulation of TGF␤RII levels, in contrast to Etsmediated epithelial differentiation during development; rather, regulation of Cdx2 expression may play a role. The villus dysmorphogenesis is independent of alterations in the crypt-villus boundary and inappropriate ␤-catenin activation, and thus appears to represent a new mechanism controlling villus architectural organization. An Analysis of animals mosaic for En/Erm expression suggests that crypt nonautonomous mechanisms underlie the crypt dysmorphogenesis phenotype. Our studies thus uncover novel Ets-regulated pathways of intestinal homeostasis in vivo. Interestingly, the overall En/Erm phenotype of disturbed crypt-villus homeostasis is consistent with recently identified Ets function(s) in the restriction of intestinal epithelial tumorigenesis.

show abstract

Targeting of the ETS Factor Gabpα Disrupts Neuromuscular Junction Synaptic Function

Cited by 28 publications

References 44 publications

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine

Contact Info

Product

Resources

About