A Self-regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning

Bénazet, Jean-Denis; Bischofberger, Mirko; Tiecke, Eva; Gonalves, Alexandre; Martin, James F.; Zuniga, Aime; Naef, Félix; Zeller, Rolf

doi:10.1007/978-3-642-12683-3_40

Cited by 47 publications

(131 citation statements)

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“…Msx1 and 2 are targets of Bmp signalling and their expression domains expand in the absence of Grem1 in homozygous null mice (Benazet et al, 2009;Khokha et al, 2003). We observed no significant change in Msx1 expression in 6 embryos (data not shown).…”

Section: Twist2 Overexpression Perturbs the Shh/grem1/fgf Autoregulatcontrasting

confidence: 69%

“…Development of the vertebrate limb is regulated by a complex network of signalling interactions that co-ordinates growth and patterning in all three axes (Benazet et al, 2009;Loomis et al, responsible for maintaining expression of the Bmp antagonist Grem1 which counters the repressive influence of Bmps on the expression of AER-Fgfs (Khokha et al, 2003;Michos et al, 2004;Verheyden and Sun, 2008;Zuniga et al, 1999). Together, these growth factors establish the core of the growth regulating network that will coordinate early outgrowth and patterning of the limb.…”

Section: Introductionmentioning

confidence: 96%

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Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1

Wade

Brinas

Welfare

et al. 2012

Developmental Biology

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Twist1 has been demonstrated to play critical roles in the early development of neural crest and mesodermally derived tissues including the limb. Twist2 has been less well characterised but its relatively late onset of expression suggests specific roles in the development of a number of organs. Expression of Twist2 within the developing limbs begins after formation of the limb bud and persists within the peripheral mesenchyme until digital rays condense. We have used RCAS-mediated overexpression in chick to investigate the function of Twist2 in limb development. Viral misexpression following injection into the lateral plate mesoderm results in a spectrum of hypoplastic limb phenotypes. These include generalized shortening of the entire limb, fusion of the autopod skeletal elements, loss of individual digits or distal truncation resulting in complete loss of the autopod. These phenotypes appear to result from a premature termination of limb outgrowth and manifest as defective growth in both the proximal-distal and anterior-posterior axes. In situ hybridisation analysis demonstrates that many components of the Shh/Grem1/Fgf regulatory loop that controls early limb growth and patterning are downregulated by Twist2 overexpression. Grem1 has a complementary expression pattern to Twist2 within the limb primordia and co-expression of both Grem1 and Twist2 results in a rescue of the Twist2 overexpression phenotype. We demonstrate that Twist proteins directly repress Grem1 expression via a regulatory element downstream of the open reading frame. These data indicate that Twist2 regulates early limb morphogenesis through a role in terminating the Shh/Grem1/Fgf autoregulatory loop.

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Section: Twist2 Overexpression Perturbs the Shh/grem1/fgf Autoregulatcontrasting

confidence: 69%

Section: Introductionmentioning

confidence: 96%

Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1

Wade

Brinas

Welfare

et al. 2012

Developmental Biology

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“…Grem1 is expressed in bone and cartilage (in particular, in the epiphyseal cartilage and the resting zone) of the skeleton [9][10][11], while Grem2 is expressed in osteoblasts during in vivo skeletogenesis (in particular, in the uppermost layers of the periosteum of embryo calvariae) [12]. Grem1 knockout mice, in addition to showing crossing with other knockout genes, have skeletal deformity [13][14][15]. Moreover, Grem1 conditional knockout mice, generated using Osteocalcin-Cre for Grem1 inactivation in mature osteoblasts, have been shown to have increased bone mass [16].…”

mentioning

confidence: 99%

BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation

et al. 2012

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Bone morphogenetic proteins (BMPs) control the expressions of many genes involved in bone formation. On the basis of our hypothesis that BMP2 stimulation-regulated gene expression plays a critical role in osteoblast differentiation, we performed genome-wide screening of messenger RNA from BMP2-treated and -untreated C2C12 cells using a DNA microarray technique. We found that the expressions of Gremlin1 and Gremlin2, which are known BMP antagonists, were bidirectionally regulated by BMP2. Gremlin1 was down-regulated by BMP2, while Gremlin2 was up-regulated in both time- and dose-dependent manners. Ablation of Gremlin1 or Gremlin2 enhanced osteoblast differentiation induced by BMP2. On the other hand, treatment with recombinant Gremlin1 inhibited BMP2-induced osteoblast differentiation. Furthermore, treatment with Smad4 siRNA and the p38 MAPK inhibitor SB203580 suppressed BMP2-induced Gremlin2 gene expression. The differential regulation of Gremlin1 and Gremlin2 gene expressions by BMP2 may explain the critical function of these genes during osteoblast differentiation.

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“…While the Hedgehog proteins themselves upregulate HHIP-1 transcription (thus constituting a negative feedback loop), the increase in HHIP-1 transcripts in hematopoietic progenitors by Gremlin1 in the present study was likely a consequence of different mechanisms, since there was no increase in the Hedgehog pathway genes interrogated. Gremlin1 induced HHIP-1 upregulation may also be a consequence of the complex regulatory interplay between BMP/Gremlin1/Hedgehog/FGF pathways [1]. Further investigation is required to identify the mechanism underlying HHIP-1 upregulation in HSC.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, Gremlins have diverse effects on several pathways including Sonic hedgehog (SHH), fibroblast growth factor (FGF), Wnt and Notch ligand expression and signaling, cell cycle control proteins and cytokine signaling [1][2][3]. Gremlin1 is expressed in normal hematopoietic tissues including the spleen [4], and has BMP-independent effects on endothelial cells and monocytes [5,6].…”

Section: Introductionmentioning

confidence: 99%

The effects of Gremlin1 on human umbilical cord blood hematopoietic progenitors

Shekels

Wanshura

Xie

et al. 2015

Blood Cells, Molecules, and Diseases

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A Self-regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning

Cited by 47 publications

References 1 publication

Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1

Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1

BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation

The effects of Gremlin1 on human umbilical cord blood hematopoietic progenitors

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