Mutation in the type IB bone morphogenetic protein receptor
            <i>alk6b</i>
            impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

Neumann, Joanie C.; Chandler, Garvin L.; Damoulis, Vanessa A.; Fustino, Nicholas J.; Lillard, Katherine; Looijenga, Leendert H. J.; Margraf, Linda R.; Rakheja, Dinesh; Amatruda, James F.

doi:10.1073/pnas.1102311108

Cited by 74 publications

(78 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a mutagenic approach, an interesting and first model of GCT in zebrafish has been generated. Forward genetic approaches showed that inactivation of Alk6, a type I Bone Morphogenic receptor, results in activation of the Smad pathway in male germ cells, and tumors composed of pre-meiotic germ cells are formed (Neumann et al, 2011a, Neumann et al, 2011b, still showing germ cell lineage characteristics.…”

Section: Zebrafishmentioning

confidence: 99%

Development of malignant germ cells - the genvironmental hypothesis

Looijenga¹,

Agthoven²,

Biermann³

2013

Int. J. Dev. Biol.

View full text Add to dashboard Cite

Human germ cell tumors are of interest because of their epidemiology, clinic and pathobiology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insight triggered development of a higher order division into five types of human germ cell tumors. In the context of male germ cells, only three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Various animal models, both occurring spontaneous or induced, are reported, of which their relevance is still a matter of debate. Recent multidisciplinary studies have led to a significant increase in our understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, particularly the seminomas and nonseminomas (Type II). This paper will discuss a number of interesting insights into the normal and aberrant regulation of germ cell development, resulting in the so-called genvironmental hypothesis. This assumes a subtle interaction between environmental-and (epi)genetic parameters, resulting in clinical/phenotypical characteristics. These influence signaling pathways and thereby developmental processes, including gonadal development, germ cell proliferation, maturation and apoptosis. In the case of a disturbed physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells, during a specific window of sensitization, might be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow a better definition of individuals at risk of developing a germ cell malignancy, and allow a better selection of scientific approaches to elucidate the corresponding pathogenesis.

show abstract

Section: Zebrafishmentioning

confidence: 99%

Development of malignant germ cells - the genvironmental hypothesis

Looijenga¹,

Agthoven²,

Biermann³

2013

Int. J. Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…To reduce yolk content, ovaries were dissected from alk6b −/− adults (Neumann et al, 2011) and lysed in RIPA buffer. To pre-clear the lysate and to bind the antibody, respectively, 500 μg ovary lysate+50 μl Protein G beads (New England Biolabs, S1430S) and 50 μl Protein-G beads+100 μl y1165 (Heim et al, 2014) were simultaneously incubated at 4°C for 1 h. Precleared lysate and antibody-bound beads were incubated at 4°C for 1 h and beads were then washed with RIPA.…”

Section: Buc Pull-downmentioning

confidence: 99%

Kinesin-1 interacts with Bucky ball to form germ cells and is required to pattern the zebrafish body axis

et al. 2015

View full text Add to dashboard Cite

In animals, specification of the primordial germ cells (PGCs), the stem cells of the germline, is required to transmit genetic information from one generation to the next. Bucky ball (Buc) is essential for germ plasm (GP) assembly in oocytes and its overexpression results in excess PGCs in zebrafish embryos. However, the mechanistic basis for the excess PGCs in response to Buc overexpression, and whether endogenous Buc functions during embryogenesis are unknown. Here we show that endogenous Buc, like GP and overexpressed Buc-GFP, accumulates at embryonic cleavage furrows. Furthermore, we show that the maternally expressed zebrafish Kinesin-1 Kif5Ba is a binding partner of Buc and that maternal kif5Ba (Mkif5Ba) plays an essential role in germline specification in vivo. Specifically, Mkif5Ba is required to recruit GP to cleavage furrows and thereby specifies PGCs. Moreover, Mkif5Ba is required to enrich Buc at cleavage furrows and for Buc’s ability to promote excess PGCs, providing mechanistic insight into how Buc functions to assemble embryonic GP. In addition, we show that Mkif5Ba is also essential for dorsoventral (DV) patterning. Specifically, Mkif5Ba promotes formation of the parallel vegetal microtubule array required to asymmetrically position dorsal determinants (DDs) towards the prospective dorsal side. Interestingly, while Syntabulin and wnt8a translocation depend on kif5Ba, grip2a translocation does not, providing evidence for two distinct mechanisms by which DDs may be asymmetrically distributed. These studies identify essential roles for maternal Kif5Ba in PGC specification and DV patterning and provide mechanistic insight into Buc functions during early embryogenesis.

show abstract

“…77 Undifferentiated human germ cell tumors showed loss of bone morphogenetic protein (BMP) signaling, suggesting that BMP signaling may influence germ cell differentiation and transformation in human and zebrafish gonads. 76 Testicular tumors have also been reported in 2 different zebrafish lines with mutations in brca2 (Table 8). In humans, carriers for pathologic BRCA2 mutations are at increased risk for tumors of reproductive organs (breast and ovary); 52,113 however, the specific association between BRCA2 mutation and reproductive tumorigenesis is not understood.…”

Section: Models Of Gonadal Neoplasiamentioning

confidence: 99%

“…33,77 Interestingly, alk6b-mutant female zebrafish did not develop ovarian tumors spontaneously, although germ cell differentiation was markedly impaired. 76,77 Rare ovarian germ cell tumors occurred in alk6b-mutant female zebrafish after exposure to DMBA. 77 Undifferentiated human germ cell tumors showed loss of bone morphogenetic protein (BMP) signaling, suggesting that BMP signaling may influence germ cell differentiation and transformation in human and zebrafish gonads.…”

Section: Models Of Gonadal Neoplasiamentioning

confidence: 99%

“…33 In comparison, zebrafish with a nonsense mutation in the type 1B bone morphogenetic protein receptor alk6b developed seminomas at a median age of 7 months. 76,77 Both tg(flck-TAg) and alk6b-mutant zebrafish showed variable degrees of differentiation in seminomas, ranging from tumors with clear spermatocytic differentiation to tumors composed of homogeneous sheets of undifferentiated neoplastic spermatogonia. 33,77 Interestingly, alk6b-mutant female zebrafish did not develop ovarian tumors spontaneously, although germ cell differentiation was markedly impaired.…”

Section: Models Of Gonadal Neoplasiamentioning

confidence: 99%

See 1 more Smart Citation

Zebrafish Models for Human Cancer

Shive

2012

Vet Pathol

View full text Add to dashboard Cite

For decades, the advancement of cancer research has relied on in vivo models for examining key processes in cancer pathogenesis, including neoplastic transformation, progression, and response to therapy. These studies, which have traditionally relied on rodent models, have engendered a vast body of scientific literature. Recently, experimental cancer researchers have embraced many new and alternative model systems, including the zebrafish (Danio rerio). The general benefits of the zebrafish model for laboratory investigation, such as cost, size, fecundity, and generation time, were quickly superseded by the discovery that zebrafish are amenable to a wide range of investigative techniques, many of which are difficult or impossible to perform in mammalian models. These advantages, coupled with the finding that many aspects of carcinogenesis are conserved in zebrafish as compared with humans, have firmly established a unique niche for the zebrafish model in comparative cancer research. This article introduces methods for generating cancer models in zebrafish and reviews a range of models that have been developed for specific cancer types. Keywords animal disease models, cancer, genetic modification, zebrafishThe zebrafish (Danio rerio) emerged as a model for scientific research in the 1930s, with many early studies devoted to the investigation of developmental processes in embryos. 53 The use of zebrafish in research has subsequently expanded into a broad range of disciplines. As a research species, zebrafish offer certain advantages over traditional vertebrate models, including rapid generation time, high fecundity, external embryonic development, a capacity for high stocking density in relatively small areas, and lower maintenance costs. 64 In recent years, the zebrafish has come into its own as a relevant comparative model for a diverse spectrum of human diseases.Although zebrafish are relative newcomers to the field of comparative cancer research, these small animals have emerged as a powerful tool for investigators. As vertebrate organisms, they share many features of embryonic development and adult anatomy that are critical for comparative animal models. 64,71 In the world of cancer research, this has important implications ranging from conserved signaling pathways and transcriptional regulatory mechanisms, to organogenesis and tissue differentiation, to cellular transformation and tumor initiation. Zebrafish cancer models have been produced by a variety of methods, leading to a broad spectrum of cancer susceptibilities in animals of multiple age groups. Flexibility in genetic manipulation, adaptability to current tools for cancer analysis, and capacity to define cellular and molecular interactions in vivo provide the zebrafish with its own very unique set of advantages for the investigation of cancer biology. Mechanisms for Developing Cancer Models in ZebrafishZebrafish cancer models have been developed by a number of mechanisms (Table 1). Although initial studies relied on chemical carcinogens for t...

show abstract

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

Cited by 74 publications

References 48 publications

Development of malignant germ cells - the genvironmental hypothesis

Development of malignant germ cells - the genvironmental hypothesis

Kinesin-1 interacts with Bucky ball to form germ cells and is required to pattern the zebrafish body axis

Zebrafish Models for Human Cancer

Contact Info

Product

Resources

About