Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo

Panagiotaki, Niki; Dajas-Bailador, Federico; Amaya, Enrique; Papalopulu, Nancy; Dorey, Karel

doi:10.1242/dev.053173

Cited by 33 publications

(40 citation statements)

References 76 publications

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“…The expression of SPRY1, 2 and 4 is ubiquitous in both embryos and adults, whereas SPRY3 is restricted to the brain and testes (Leeksma et al, 2002; Minowada et al, 1999; Panagiotaki et al, 2010). Though evidence suggests that RTK signaling regulates the expression levels of SPRY2 (Cabrita and Christofori, 2008), it is not clear whether other types of regulation are involved.…”

Section: Discussionmentioning

confidence: 99%

PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively

Zhu

Nelson

2013

Developmental Biology

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The tree-like architecture of the mammary gland is generated by branching morphogenesis, which is regulated by many signals from the microenvironment. Here we examined how signaling downstream of phosphoinositide 3-kinase (PI3K) regulates different steps of mammary branching using three-dimensional culture models of the mammary epithelial duct. We found that PI3K was required for both branch initiation and elongation. Activated Akt was enhanced at branch initiation sites where its negative regulator, PTEN, was blocked by signaling via Sprouty2 (SPRY2); inhibiting Akt prevented branch initiation. The pattern of SPRY2 expression, and thus of Akt activation and branch initiation, was controlled by mechanical signaling from endogenous cytoskeletal contractility. In contrast, activated GTP-bound Rac1 localized to the leading edge of nascent branches and was required for branch elongation. These data suggest that the PI3K network integrates mechanical and biochemical signaling to control branching morphogenesis of mammary epithelial cells.

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Section: Discussionmentioning

confidence: 99%

PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively

Zhu

Nelson

2013

Developmental Biology

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“…Here, we hypothesized that members of the Sprouty family, which encode intracellular RTK signaling inhibitors essential for numerous vertebrate developmental processes (27)(28)(29)(30), regulate EGFR signaling in the mammary gland stroma. To test this hypothesis, we determined the mammary gland phenotype in mice lacking sprouty 1 (Spry1) and analyzed the mechanisms by which SPRY1 functions.…”

Section: Significancementioning

confidence: 99%

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Koledová

Zhang

Streuli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The role of the local microenvironment in influencing cell behavior is central to both normal development and cancer formation. Here, we show that sprouty 1 (SPRY1) modulates the microenvironment to enable proper mammary branching morphogenesis. This process occurs through negative regulation of epidermal growth factor receptor (EGFR) signaling in mammary stroma. Loss of SPRY1 resulted in up-regulation of EGFR-extracellular signal-regulated kinase (ERK) signaling in response to amphiregulin and transforming growth factor alpha stimulation. Consequently, stromal paracrine signaling and ECM remodeling is augmented, leading to increased epithelial branching in the mutant gland. By contrast, down-regulation of EGFR-ERK signaling due to gain of Sprouty function in the stroma led to stunted epithelial branching. Taken together, our results show that modulation of stromal paracrine signaling and ECM remodeling by SPRY1 regulates mammary epithelial morphogenesis during postnatal development.branching morphogenesis | FGF signaling | EGF signaling | epithelial-stromal interactions | stromal microenvironment A central theme in developmental and cancer biology research is to understand the mechanisms by which the local microenvironment, or niche, influences fundamental aspects of cell and tissue behavior during organ formation and function (1). The importance of mesenchyme, as the embryonic niche, in determining organ identity and fate of the epithelium was demonstrated long ago by classic embryological studies (2, 3). More recent studies have shown, however, that postnatal stroma, a derivative of embryonic mesenchyme, is essential for maintenance of cell fate and differentiation status in adult life (4, 5). Indeed, abnormal stroma can lead to the formation of a cancer microenvironment, and it plays a causative role during tumor onset and progression (1, 6). As such, understanding postnatal stromal biology and the mechanism by which its deregulation may promote tumorigenesis is of key importance.The mouse mammary gland is a powerful model for understanding the genetic and cellular basis of stromal biology (7). The observation that epithelial branching of the mammary gland persists for many weeks after birth has made amenable the detection of stromal influences on epithelial invasion and patterning (8, 9). Indeed, postnatal mammary stroma is composed of many cell types, including periductal fibroblasts and white adipocytes, endothelial cells, nerve cells, and a variety of infiltrating immune cells, including macrophages and eosinophils, which play an important role in postnatal branching (10).Mammary stroma regulates epithelial branching by at least two mechanisms. Stromal cells produce several paracrine factors, including fibroblast growth factors (FGFs) and insulin-like growth factor (IGF) that activate receptor tyrosine kinases (RTK) (11, 12). For example, a reduction in FGF signaling due to loss of FGF10 or its receptor FGF receptor 1/2 (FGFR1/2), or reduced IGF signaling, leads to stunted epithelial branching (13-16). B...

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“…BDNF promotes dendritic arbor growth (Ozdinler and Macklis, 2006; Reichardt, 2006; Wang et al, 2015) and axonal branching (Panagiotaki et al, 2010) by binding to TrkB (Bramham, 2008; Park and Poo, 2013), a receptor tyrosine kinase (Cohen-Cory and Fraser, 1995; McAllister et al, 1999). The binding of BDNF stimulates trans-phosphorylation of multiple Tyr residues, which triggers multiple downstream pathways, including activation of the small Rho family GTPase, Rac1 (Huang and Reichardt, 2003; Minichiello, 2009).…”

Section: Introductionmentioning

confidence: 99%

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

2016

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Exogenous brain-derived neurotrophic factor (BDNF), acting through TrkB, is known to promote neurite formation and branching. This response to BDNF was eliminated by inhibition of TrkB kinase and by specific inhibition of the GEF1 domain of Kalirin, which activates Rac1. Neurons from Kalrn knockout mice were unable to activate Rac1 in response to BDNF. BDNF-triggered neurite outgrowth was abolished when Kalrn expression was reduced using shRNA that targets all of the major Kalrn isoforms, and reduced in neurons from Kalrn knockout mice. The Kalrn isoforms expressed early in development also include a GEF2 domain that activates RhoA. However, BDNF-stimulated neurite outgrowth in Kalrn knockout neurons was rescued by expression of Kalirin-7, which includes only the GEF1 domain but lacks the GEF2 domain. Dendritic morphogenesis, which requires spatially restricted, coordinated changes in the actin cytoskeleton and in the organization of microtubules, involves essential contributions from multiple Rho GEFs. Since Tiam1, another Rho GEF, is also required for BDNF-stimulated neurite outgrowth, an inhibitory fragment of Tiam1 (PHn-CC-EX) was tested and found to interfere with both Kalirin and Tiam1 GEF activity. The prolonged TrkB activation observed in response to BDNF in Kalrn knockout neurons and the altered time course and extent of ERK, CREB and Akt activation observed in the absence of Kalrn would be expected to alter the response of these neurons to other regulatory factors.

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Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo

Cited by 33 publications

References 76 publications

PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively

PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

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