R N Kelsh

..INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking...

..The combination of pigmentation and enteric nervous system defects makes colourless mutations a model for two human neurocristopathies, Waardenburg-Shah syndrome and Hirschsprung's disease...

..Here, I discuss this controversy and argue that these functions are, in part, molecularly interrelated...

..As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern. SOX10 expression is highly conserved between all vertebrates characterised...

..Initial 'evo-devo' studies indicate how fish pigment patterns may evolve and will become more complete as the developmental genetics is integrated with theoretical modelling...

..Furthermore, their distribution indicates a defect in melanoblast dispersal. These observations permit us to refine our model of the genetic control of melanophore development in zebrafish embryos...

..Finally, we provide a brief outline of how the evolutionary emergence of neural crest potentiality may have proceeded, and how it may be investigated...

..These mutants will be a valuable resource for pigment cell and neural crest studies and will strongly complement the mutant collections in other vertebrates...

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..Their function in the patterning of the ventrolateral mesoderm and the induction of the neuroectoderm is similar to the function of the Spemann organizer in the amphibian embryo...

..In combination with the embryological advantages of zebrafish, these mutations should permit cellular and molecular dissection of many aspects of neural crest development...

..In an appendix to this study we list mutants showing alterations in the size of the eyes and abnormal differentiation of the lenses...

..This pathway provides ventral positional information, counteracting the dorsalizing instructions of the organizer, which is localized in the dorsal shield...

..Mutations in two genes, nevermind (nev) and macho (mao), affect axonal projection in the optic tectum, whereas axon formation and elongation of motorneurons are disrupted by mutations in the diwanka (diw) and the unplugged (unp) genes...

..Mutants in kugelig (kgg) do not form the yolk tube at the posterior side of the yolk sac...

..In addition to the four mutants with defects in early notochord formation, we have isolated 84 mutants, defining at least 15 genes, with defects in later stages of notochord development. These are listed in an appendix to this study...

..The mutations presented here could serve as an entry point to the establishment of a genetic hierarchy underlying organogenesis...

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..As a working hypothesis, we propose that midline-group genes may act to maintain proper structure and inductive function of zebrafish midline tissues...

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..These mutations may affect xanthophore pigment distribution within the cells or xanthophore cell shape. Mutations in seven genes affecting xanthophore pigmentation remain unclassified...

..Our results confirm and extend a previous report, and show that at least one member of this conserved signalling pathway is required for formation of the boundary between midbrain and hindbrain in the zebrafish...

..Stein und bein (sub) has reduced dorsal and pelvic fins, whereas finless (fls) and wanda (wan) mutants affect all adult fins. Finally, mutations in four genes causing defects in embryonic skin formation will be briefly reported...

..This suggests a novel mechanism for the aetiology of Waardenburg-Shah syndrome in which affected neural crest derivatives fail to be generated from the neural crest...

..The mutants presented here may be valuable tools for elucidating the genetic mechanisms that underlie the development of the mandibular and the hyoid arches, as well as the process of cartilage differentiation...

..These results suggest that focal cell death may be a useful clue for the detection of early patterning defects of the vertebrate nervous system in regions devoid of visible landmarks...

..The analysis of these mutants provides a powerful approach towards defining the molecular mechanisms involved in vertebrate hematopoietic development...

..Furthermore, the dominant zygotic-maternal effect phenotypes illustrate the maternal and zygotic interplay of genes that orchestrate the early cell movements of the zebrafish...

..Expression in colourless mutant embryos is consistent with these cells being satellite glia and Schwann cells...

..However, in addition, we trace back the sox10 mutant ENS defect to an even earlier time point, finding that most neural crest cells fail to migrate ventrally to the gut primordium...

..In conjunction with previous findings, these data establish the generality of our model of Sox10 function in NC fate specification...

..We propose that the dominant melanophore phenotype in Waardenburg syndrome IV individuals with SOX10 mutations is likely to result from failure to activate MITF in the normal number of melanoblasts...

..Here we give an overview of the spectrum of mutant phenotypes obtained, and discuss the limits and the potentials of a genetic saturation screen in the zebrafish...

..We thus identify Sdf1 as a key molecule in pigment pattern formation, adding to the growing inventory of its roles in embryonic development...

..In summary, we have discovered a novel signalling pathway in NCC development and demonstrate fate specification of iridophores as the first identified role for Ltk...

..We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear...

..There is still a wealth of zebrafish mutations whose molecular bases remain unknown, and it is likely that the revelation of the underlying genes will both broaden and alter our understanding of specification within the neural crest...

..Together, analysis of these issues will clarify this expanding, but still young, field and contribute to exploration of the important therapeutic potential of these cells...

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..However, our results further suggest that, although FGF signaling is required for the realization of the ectomesenchymal lineages, other cues from the pharyngeal epithelia are also likely to be involved...

..The runx2b pebp2alphaA2 isoform induces osteocalcin gene expression by binding to a specific region of the promoter and seems to have been selectively conserved in the teleost lineage...

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..Phenotypes induced by injection of antisense morpholinos against both Gfra orthologs can be rescued by introduction of mRNA for gfra1a or for gfra2, suggesting that GFRalpha1 and GFRalpha2 are functionally equivalent...

..These two models will, in combination, be a powerful system for studies of the embryogenesis and evolution of pigmentation...

..These studies will direct further analyses of Sox10 regulation and provide candidate sequences for mutation detection in WS4 patients lacking a SOX10-coding mutation...

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..1 Strikingly this study identifies the human orthologue, SLC24A5, as likely to make a major contribution to the pale skin colouration of Western Europeans...

..These results suggest different patterns of Mgp accumulation between fish and mammals...