FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

Hong, Sung-Kook; Dawid, Igor B.

doi:10.1073/pnas.0812880106

Cited by 85 publications

(93 citation statements)

References 48 publications

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“…Recent studies have shown that FGF signaling is required for morphogenesis and ciliogenesis of the KV as well as for LR patterning (2,8,15). Although knockdown of the FGF target genes ier2 and fibp1 is known to interfere with DFC formation (15), the contribution of FGF signaling before KV formation is poorly understood.…”

Section: Resultsmentioning

confidence: 99%

“…Accumulated evidence points to crucial roles of FGF signaling in several processes of LR asymmetric patterning (2,8,9,15,21,22). Two recent studies, in particular, have shown that FGF signaling regulates KV ciliogenesis during LR pattering (8,15).…”

Section: Discussionmentioning

confidence: 99%

“…At the end of gastrulation, DFCs differentiate into ciliated epithelial cells of the KV, which generates the nodal flow required for LR patterning (7,12,13). Recent studies have shown that FGF signaling is required for morphogenesis and ciliogenesis of the KV as well as for LR patterning (2,8,15). Although knockdown of the FGF target genes ier2 and fibp1 is known to interfere with…”

Section: Positive Feedback Loop Of Fgf Signaling Mediated By Cnpy1 Ismentioning

confidence: 99%

“…2F and SI Appendix, Fig. S6F) (8,15). To test for a functional relationship between FGF signaling and cnpy1 in DFC clustering, we analyzed whether the loss of FGF signaling function could phenocopy cnpy1 morphants.…”

Section: Cnpy1 Function Within Dfcs Is Essential For Kv Ciliogenesis mentioning

confidence: 99%

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Canopy1, a positive feedback regulator of FGF signaling, controls progenitor cell clustering during Kupffer's vesicle organogenesis

Matsui

Thitamadee

Murata

et al. 2011

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

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The assembly of progenitor cells is a crucial step for organ formation during vertebrate development. Kupffer's vesicle (KV), a key organ required for the left-right asymmetric body plan in zebrafish, is generated from a cluster of ∼20 dorsal forerunner cells (DFCs). Although several genes are known to be involved in KV formation, how DFC clustering is regulated and how cluster formation then contributes to KV formation remain unclear. Here we show that positive feedback regulation of FGF signaling by Canopy1 (Cnpy1) controls DFC clustering. Cnpy1 positively regulates FGF signals within DFCs, which in turn promote Cadherin1-mediated cell adhesion between adjacent DFCs to sustain cell cluster formation. When this FGF positive feedback loop is disrupted, the DFC cluster fails to form, eventually leading to KV malformation and defects in the establishment of laterality. Our results therefore uncover both a previously unidentified role of FGF signaling during vertebrate organogenesis and a regulatory mechanism underlying cell cluster formation, which is an indispensable step for formation of a functional KV and establishment of the left-right asymmetric body plan.left-right patterning | ciliogenesis F ibroblast growth factor (FGF) signaling plays crucial roles in multiple morphogenetic processes of vertebrate development, including gastrulation movement, mesoderm formation, and leftright (LR) patterning (1-3). Because gain or loss of function of FGF signaling results in morphological changes in the embryo, some mechanism must ensure appropriate FGF signal levels in space and time for proper morphogenesis throughout development. FGF effectors acting as positive or negative regulators show a wide range of expression patterns and activities, contributing to the precise regulation of FGF signal activity (1, 4). Although most effectors identified to date act as negative regulators of FGF signaling, a few that positively regulate FGF activity have been reported (1, 4).We recently identified in zebrafish a positive regulator of FGF signaling named canopy1 (cnpy1), which is required for maintenance of the midbrain-hindbrain boundary (MHB) (5). Expression of cnpy1 was restricted to the MHB at late-somitogenesis stages, whereas cnpy1 was broadly distributed in earlier embryos (5) (SI Appendix, Fig. S1A), suggesting an additional role(s) for Cnpy1-mediated FGF signaling beyond the regulation of MHB formation. In this study, we characterize cnpy1 in detail during early zebrafish development and show that a Cnpy1-mediated positive feedback loop of FGF signaling promotes cell cluster formation between dorsal forerunner cells (DFCs) during gastrulation. We also demonstrate that the failure of DFCs to cluster when this FGF positive loop is disrupted eventually leads to Kupffer's vesicle (KV) malformation and randomization of LR asymmetric patterning. Results Positive Feedback Loop of FGF Signaling Mediated by Cnpy1 IsActivated Specifically in DFCs During Zebrafish Gastrulation. To reveal the role of Cnpy1-mediated FGF signaling in ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Positive Feedback Loop Of Fgf Signaling Mediated By Cnpy1 Ismentioning

confidence: 99%

Section: Cnpy1 Function Within Dfcs Is Essential For Kv Ciliogenesis mentioning

confidence: 99%

See 2 more Smart Citations

Canopy1, a positive feedback regulator of FGF signaling, controls progenitor cell clustering during Kupffer's vesicle organogenesis

Matsui

Thitamadee

Murata

et al. 2011

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

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“…Ier2 expression also correlates with cell differentiation, for example, during neuronal differentiation of PC12 and H19-7 cells (Charles et al, 1990;Eschelbach et al, 1998;Chung et al, 1998), and after TPA-induced differentiation of HL-60 cells (Shimizu et al, 1991). During embryonic development, Ier2 has been reported to determine left-right asymmetry patterning in an fibroblast growth factor (FGF)-dependent manner through interacting with fibp1 (Hong and Dawid, 2009). …”

Section: Ier2 Expression Promotes Invasiveness Of 1as Tumor Cellsmentioning

confidence: 99%

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

et al. 2011

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Here, we report unbiased screens for genes expressed in metastatic tumor cells that are associated with cell motility. These screens identified Ier2, an immediate early gene of unknown function, as potentially having a role in tumor cell motility and metastasis. Knockdown of Ier2 in 3T3 fibroblasts inhibited their motility upon relief of contact inhibition in monolayer wounding assays. Furthermore, ectopic Ier2 expression promoted the motility and invasiveness of poorly metastatic 1AS pancreatic tumor cells in vitro. Relief of contact inhibition was associated with translocation of the Ier2 protein from the cytoplasm to the nucleus in both 3T3 fibroblasts and 1AS tumor cells. Importantly, ectopic Ier2 expression in 1AS cells stimulated metastasis formation when cells were implanted into experimental animals. Furthermore, we found elevated Ier2 expression in a wide variety of human tumor types. This correlated with poor metastasis-free and overall survival in patients with colorectal adenocarcinomas. Together, these data reveal Ier2 as a new player in the regulation of tumor progression and metastasis, and suggest that Ier2 may be useful prognostically and therapeutically in the management of cancer.

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Ciliary biology: Understanding the cellular and genetic basis of human ciliopathies

Cárdenas-Rodríguez

Badano

2009

American J of Med Genetics Pt C

147

152

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Motile cilia have long been known to play a role in processes such as cell locomotion and fluid movement whereas the functions of primary cilia have remained obscure until recent years. To date, ciliary dysfunction has been shown to be causally linked to a number of clinical manifestations that characterize the group of human disorders known as ciliopathies. This classification reflects a common or shared cellular basis and implies that it is possible to associate a series of different human conditions with ciliary dysfunction, which allows gaining insight into the cellular defect in disorders of unknown etiology solely based on phenotypic observations. Furthermore, to date we know that the cilium participates in a number of biological processes ranging from chemo-and mechanosensation to the transduction of a growing list of paracrine signaling cascades that are critical for the development and maintenance of different tissues and organs. Consequently, the primary cilium has been identified as a key structure necessary to regulate and maintain cellular and tissue homeostasis and thus its study is providing significant information to understand the pathogenesis of the different phenotypes that characterize these human conditions. Finally, the similarities between different ciliopathies at the phenotypic level are proving to be due to their shared cellular defect and also their common genetic basis. To this end, recent studies are showing that mutations in a given ciliary gene often appear involved in the pathogenesis of more than one clinical entity, complicating their genetic dissection, and hindering our ability to generate accurate genotype-phenotype correlations. ß

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FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

Cited by 85 publications

References 48 publications

Canopy1, a positive feedback regulator of FGF signaling, controls progenitor cell clustering during Kupffer's vesicle organogenesis

Canopy1, a positive feedback regulator of FGF signaling, controls progenitor cell clustering during Kupffer's vesicle organogenesis

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

Ciliary biology: Understanding the cellular and genetic basis of human ciliopathies

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