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C B Kimmel

Publications and source records attributed to C B Kimmel.

At least 19 recordsLinked to original sources
PubMed2001

Specification and morphogenesis of the zebrafish larval head skeleton.

Forward genetic analyses can reveal important developmental regulatory genes and how they function to pattern morphology. This is because a mutated gene can produce a novel, sometimes beautiful, phenotype that, like the normal phenotype, immediately seems worth understanding. Generally the loss-of-function mutant phenotype is simplified from the wild-type one, and often the nature of the pattern simplification allows one to deduce how the wild-type gene contributes to patterning the normal, more complex, morphology. This truism seems no less valid for the vertebrate head skeleton than for other and simpler cases of patterning in multicellular plants and animals. To show this, we review selected zebrafish craniofacial mutants. "Midline group" mutations, in genes functioning in one of at least three signal transduction pathways, lead to neurocranial pattern truncations that are primarily along the mediolateral axis. Mutation of lazarus/pbx4, encoding a hox gene partner, and mutation of valentino/kreisler, a hox gene regulator, produce anterior-posterior axis disruptions of pharyngeal cartilages. Dorsoventral axis patterning of the same cartilages is disrupted in sucker/endothelin-1 mutants. We infer that different signal transduction pathways pattern cartilage development along these three separate axes. Patterning of at least the anterior-posterior and dorsoventral axes have been broadly conserved, e.g., reduced Endothelin-1 signaling similarly perturbs cartilage specification in chick, mouse, and zebrafish. We hypothesize that Endothelin-1 also is an upstream organizer of the patterns of cellular interactions during cartilage morphogenesis.

Animals↗
PubMed2000

islet reveals segmentation in the Amphioxus hindbrain homolog.

The vertebrate embryonic hindbrain is segmented into rhombomeres. Gene expression studies suggest that amphioxus, the closest invertebrate relative of vertebrates, has a hindbrain homolog. However, this region is not overtly segmented in amphioxus, raising the question of how hindbrain segmentation arose in chordate evolution. Vertebrate hindbrain segmentation includes the patterning of cranial motor neurons, which can be identified by their expression of the LIM-homeodomain transcription factor islet1. To learn if the amphioxus hindbrain homolog is cryptically segmented, we cloned an amphioxus gene closely related to islet1, which we named simply islet. We report that amphioxus islet expression includes a domain of segmentally arranged cells in the ventral hindbrain homolog. We hypothesize that these cells are developing motor neurons and reveal a form of hindbrain segmentation in amphioxus. Hence, vertebrate rhombomeres may derive from a cryptically segmented brain present in the amphioxus/vertebrate ancestor. Other islet expression domains provide evidence for amphioxus homologs of the pineal gland, adenohypophysis, and endocrine pancreas. Surprisingly, homologs of vertebrate islet1-expressing spinal motor neurons and Rohon-Beard sensory neurons appear to be absent.

Amino Acid Sequence↗
PubMed2000

lazarus is a novel pbx gene that globally mediates hox gene function in zebrafish.

Individual vertebrate Hox genes specify aspects of segment identity along the anterior-posterior axis. The exquisite in vivo specificity of Hox proteins is thought to result from their interactions with members of the Pbx/Exd family of homeodomain proteins. Here, we report the identification and cloning of a zebrafish gene, lazarus, which is required globally for segmental patterning in the hindbrain and anterior trunk. We show that lazarus is a novel pbx gene and provide evidence that it is the primary pbx gene required for the functions of multiple hox genes during zebrafish development. lazarus plays a critical role in orchestrating the corresponding segmentation of the hindbrain and the pharyngeal arches, a key step in the development of the vertebrate body plan.

Animals↗
PubMed2000

sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development.

Mutation of sucker (suc) disrupts development of the lower jaw and other ventral cartilages in pharyngeal segments of the zebrafish head. Our sequencing, cosegregation and rescue results indicate that suc encodes an Endothelin-1 (Et-1). Like mouse and chick Et-1, suc/et-1 is expressed in a central core of arch paraxial mesoderm and in arch epithelia, both surface ectoderm and pharyngeal endoderm, but not in skeletogenic neural crest. Long before chondrogenesis, suc/et-1 mutant embryos have severe defects in ventral arch neural crest expression of dHAND, dlx2, msxE, gsc, dlx3 and EphA3 in the anterior arches. Dorsal expression patterns are unaffected. Later in development, suc/et-1 mutant embryos display defects in mesodermal and endodermal tissues of the pharynx. Ventral premyogenic condensations fail to express myoD, which correlates with a ventral muscle defect. Further, expression of shh in endoderm of the first pharyngeal pouch fails to extend as far laterally as in wild types. We use mosaic analyses to show that suc/et-1 functions nonautonomously in neural crest cells, and is thus required in the environment of postmigratory neural crest cells to specify ventral arch fates. Our mosaic analyses further show that suc/et-1 nonautonomously functions in mesendoderm for ventral arch muscle formation. Collectively our results support a model for dorsoventral patterning of the gnathostome pharyngeal arches in which Et-1 in the environment of the postmigratory cranial neural crest specifies the lower jaw and other ventral arch fates.

Amino Acid Sequence↗
PubMed1998

The shaping of pharyngeal cartilages during early development of the zebrafish.

In zebrafish the cartilages of the pharynx develop during late embryogenesis and grow extensively in the larva before eventually being replaced by bone. Here we examine chondrocyte arrangements, shapes, numbers, and divisions in the young hyoid cartilages. We observe two distinct developmental phases, morphogenesis and growth. The first phase generates stereotypically oriented chondrocyte stacks that might form by intercalations among cells within the precartilage condensations. In mutants that have deformed cartilages the orientation of the stacks is changed, and we propose that their correct formation underlies the correct initial shaping of the organ. The following period of rapid, nearly isometric cartilage growth occurs by divisions of chondrocytes that are largely located near the joints, and appears to be under quite separate regulation.

Animals↗
PubMed1998

An amphioxus snail gene: expression in paraxial mesoderm and neural plate suggests a conserved role in patterning the chordate embryo.

Homologs of the Drosophila snail gene have been characterized in several vertebrates. In addition to being expressed in mesoderm during gastrulation, vertebrate snail genes are also expressed in presumptive neural crest and/or its derivatives. Given that neural crest is unique to vertebrates and is considered to be of fundamental importance in their evolution, we have cloned and characterized the expression of a snail gene from amphioxus, a cephalochordate widely accepted as the sister group of the vertebrates. We show that, at the amino acid sequence level, the amphioxus snail gene is a clear phylogenetic outgroup to all the characterized vertebrate snail genes. During embryogenesis snail expression initially becomes restricted to the paraxial or presomitic mesoderm of amphioxus. Later, snail is expressed at high levels in the lateral neural plate, where it persists during neurulation. Our results indicate that an ancestral function of snail genes in the lineage leading to vertebrates is to define the paraxial mesoderm. Furthermore, our results indicate that a cell population homologous to the vertebrate neural crest may be present in amphioxus, thus providing an important link in the evolution of this key vertebrate tissue.

Amino Acid Sequence↗
PubMed1998

Genetic analysis of chromosomal rearrangements in the cyclops region of the zebrafish genome.

Genetic screens in zebrafish have provided mutations in hundreds of genes with essential functions in the developing embryo. To investigate the possible uses of chromosomal rearrangements in the analysis of these mutations, we genetically characterized three gamma-ray induced alleles of cyclops (cyc), a gene required for development of midline structures. We show that cyc maps near one end of Linkage Group 12 (LG 12) and that this region is involved in a reciprocal translocation with LG 2 in one gamma-ray induced mutation, cyc(b213). The translocated segments together cover approximately 5% of the genetic map, and we show that this rearrangement is useful for mapping cloned genes that reside in the affected chromosomal regions. The other two alleles, cyc(b16) and cyc(b229), have deletions in the distal region of LG 12. Interestingly, both of these mutations suppress recombination between genetic markers in LG 12, including markers at a distance from the deletion. This observation raises the possibility that these deletions affect a site required for meiotic recombination on the LG 12 chromosome. The cyc(b16) and cyc(b229) mutations may be useful for balancing other lethal mutations located in the distal region of LG 12. These results show that chromosomal rearrangements can provide useful resources for mapping and genetic analyses in zebrafish.

Alleles↗
PubMed1998

Molecular identification of spadetail: regulation of zebrafish trunk and tail mesoderm formation by T-box genes.

Inhibition of fibroblast growth factor (FGF) signaling prevents trunk and tail formation in Xenopus and zebrafish embryos. While the T-box transcription factor Brachyury (called No Tail in zebrafish) is a key mediator of FGF signaling in the notochord and tail, the pathways activated by FGF in non-notochordal trunk mesoderm have been uncertain. Previous studies have shown that the spadetail gene is required for non-notochordal trunk mesoderm formation; spadetail mutant embryos have major trunk mesoderm deficiencies, but relatively normal tail and notochord development. We demonstrate here that spadetail encodes a T-box transcription factor with homologues in Xenopus and chick. Spadetail is likely to be a key mediator of FGF signaling in trunk non-notochordal mesoderm, since spadetail expression is regulated by FGF signaling. Trunk and tail development are therefore dependent upon the complementary actions of two T-box genes, spadetail and no tail. We show that the regulatory hierarchy among spadetail, no tail and a third T-box gene, tbx6, are substantially different during trunk and tail mesoderm formation, and propose a genetic model that accounts for the regional phenotypes of spadetail and no tail mutants.

Amino Acid Sequence↗
PubMed1998

Zebrafish paraxial protocadherin is a downstream target of spadetail involved in morphogenesis of gastrula mesoderm.

Zebrafish paraxial protocadherin (papc) encodes a transmembrane cell adhesion molecule (PAPC) expressed in trunk mesoderm undergoing morphogenesis. Microinjection studies with a dominant-negative secreted construct suggest that papc is required for proper dorsal convergence movements during gastrulation. Genetic studies show that papc is a close downstream target of spadetail, gene encoding a transcription factor required for mesodermal morphogenetic movements. Further, we show that the floating head homeobox gene is required in axial mesoderm to repress the expression of both spadetail and papc, promoting notochord and blocking differentiation of paraxial mesoderm. The PAPC structural cell-surface protein may provide a link between regulatory transcription factors and the actual cell biological behaviors that execute morphogenesis during gastrulation.

Amino Acid Sequence↗
PubMed1998

Equivalence in the genetic control of hindbrain segmentation in fish and mouse.

The vertebrate hindbrain is subdivided into a series of rhombomeres whose segmental organization serves to pattern the architecture and innervation of the developing head. The zebrafish gene valentino is required cell-autonomously in the development of rhombomeres 5 and 6, and valentino mutants lack visible hindbrain segmentation caudal to the r3/4 boundary (Moens, C. B., Yan, Y.-L., Appel, B., Force, A. G., and Kimmel, C. B. (1996) Development 122, 3981-3990). Here we show that valentino is the zebrafish homologue of the mouse segmentation gene kreisler, which encodes a bZip transcription factor. The valentino gene is expressed in a manner consistent with its proposed role in subdividing rhombomeres 5 and 6 from their common precursor 'proto-segment' in the presumptive hindbrain, a process that we also demonstrate is reflected in the normal order of appearance of rhombomere boundaries. As well as having similar phenotypes with respect to visible hindbrain segmentation and patterns of marker gene expression, valentino and kreisler mutants have similar pharyngeal arch and inner ear defects, consistent with a conserved role for this gene in hindbrain segmentation and in patterning of the head periphery.

Amino Acid Sequence↗
PubMed1998

Zebrafish hox genes: expression in the hindbrain region of wild-type and mutants of the segmentation gene, valentino.

The developing hindbrain is organized into a series of segments termed rhombomeres which represent lineage restricted compartments correlating with domains of gene expression and neuronal differentiation. In this study, we investigate the processes of hindbrain segmentation and the acquisition of segmental identity by analyzing the expression of zebrafish hox genes in the hindbrains of normal fish and fish with a loss-of-function mutation in the segmentation gene valentino (val, the homologue of mouse kreisler; Moens, C. B., Cordes, S. P. Giorgianni, M. W., Barsh, G. S. and Kimmel, C. B. (1998). Development 125, 381-391). We find that zebrafish hox genes generally have similar expression profiles to their murine and avian counterparts, although there are several differences in timing and spatial extent of expression which may underlie some of the functional changes that have occurred along the separate evolutionary lineages of teleosts and tetrapods. Our analysis of hox gene expression in val- embryos confirms that the val gene product is important for subdivision of the presumptive rhombomere 5 and 6 territory into definitive rhombomeres, suggests that the val gene product plays a critical role in regulating hox gene transcription, and indicates that some neural crest cells are inappropriately specified in val- embryos. Our analysis of gene expression at several developmental stages has allowed us to infer differences between primary and secondary defects in the val mutant: we find that extended domains of expression for some hox genes are secondary, late phenomena potentially resulting from inappropriate cell mixing or lack of normal inter-rhombomeric interactions in the caudal hindbrain.

Amino Acid Sequence↗
PubMed1998

Promoting notochord fate and repressing muscle development in zebrafish axial mesoderm.

Cell fate decisions in early embryonic cells are controlled by interactions among developmental regulatory genes. Zebrafish floating head mutants lack a notochord; instead, muscle forms under the neural tube. As shown previously, axial mesoderm in floating head mutant gastrulae fails to maintain expression of notochord genes and instead expresses muscle genes. Zebrafish spadetail mutant gastrulae have a nearly opposite phenotype; notochord markers are expressed in a wider domain than in wild-type embryos and muscle marker expression is absent. We examined whether these two phenotypes revealed an antagonistic genetic interaction by constructing the double mutant. Muscle does not form in the spadetail;floating head double mutant midline, indicating that spadetail function is required for floating head mutant axial mesoderm to transfate to muscle. Instead, the midline of spadetail;floating head double mutants is greatly restored compared to that of floating head mutants; the floor plate is almost complete and an anterior notochord develops. In addition, we find that floating head mutant cells can make both anterior and posterior notochord when transplanted into a wild-type host, showing that enviromental signals can override the predisposition of floating head mutant midline cells to make muscle. Taken together, these results suggest that repression of spadetail function by floating head is critical to promote notochord fate and prevent midline muscle development, and that cells can be recruited to the notochord by environmental signals.

Animals↗
PubMed1997

Temporal separation in the specification of primary and secondary motoneurons in zebrafish.

In zebrafish there are two populations of motoneurons, primary and secondary, that are temporally separate in their development. To determine if midline cells play a role in the specification of these neurons, we analyzed both secondary and primary motoneurons in mutants lacking floor plate, notochord, or both floor plate and notochord. Our data show that the specification of secondary motoneurons, those most similar to motoneurons in birds and mammals, depends on the presence of either a differentiated floor plate or notochord. In the absence of both of these structures, secondary motoneurons fail to form. In contrast, primary motoneurons, early developing motoneurons found in fish and amphibians, can develop in the absence of both floor plate and notochord. A spatial correspondence is found between secondary motoneurons and sonic hedgehog-expressing floor plate and notochord. In contrast, primary motoneuronal specification depends on the presence of sonic hedgehog in gastrula axial mesoderm, the tissue that will give rise to the notochord. These results suggest that both primary and secondary motoneurons are specified by signals from midline tissues, but at very different stages of embryonic development.

Animals↗
PubMed1997

Genetic interactions in zebrafish midline development.

Mutational analyses have shown that the genes no tail (ntl, Brachyury homolog), floating head (flh, a Not homeobox gene), and cyclops (cyc) play direct and essential roles in the development of midline structures in the zebrafish. In both ntl and flh mutants a notochord does not develop, and in cyc mutants the floor plate is nearly entirely missing. We made double mutants to learn how these genes might interact. Midline development is disrupted to a greater extent in cyc;flh double mutants than in either cyc or flh single mutants; their effects appear additive. Both the notochord and floor plate are completely lacking, and other phenotypic disturbances suggest that midline signaling functions are severely reduced. On the other hand, trunk midline defects in flh;ntl double mutants are not additive, but are most often similar to those in ntl single mutants. This finding reveals that loss of ntl function can suppress phenotypic defects due to mutation at flh, and we interpret it to mean that the wild-type allele of ntl (ntl+) functions upstream to flh in a regulatory hierarchy. Loss of function of ntl also strongly suppresses the floor plate deficiency in cyc mutants, for we found trunk floor plate to be present in cyc;ntl double mutants. From these findings we propose that ntl+ plays an early role in cell fate choice at the dorsal midline, mediated by the Ntl protein acting to antagonize floor plate development as well as to promote notochord development.

Animals↗
PubMed1997

Spatial regulation of floating head expression in the developing notochord.

The zebrafish homeobox gene floating head (flh) is essential for notochord development and is one of the earliest genes to be expressed in notochord precursors. To understand how flh is regulated during notochord development, we compared the wild-type flh expression pattern to that in embryos mutant for flh and no tail (ntl), the zebrafish homologue of Brachyury. In the early gastrula, the pattern of flh expression is not affected in either flh or ntl mutants, implying that the initial establishment of a gastrula notochord domain is independent of the function of these genes. However, flh RNA is expressed at lower levels in flh mutants suggesting that flh positively regulates its own expression. During gastrulation, flh mutants show an abrupt loss of flh expression in cells which have involuted and entered the hypoblast, while the rest of the expression pattern appears normal, thus flh+ function is specifically required to maintain flh expression in hypoblast cells. The anterior-most part of the notochord rudiment differentially maintains flh expression in both wild types and flh mutant embryos, suggesting that there is unique regulation of flh in this region of the developing notochord. In ntl mutants the spatial pattern of flh expression is altered as early as the late gastrula stage, becoming broad and diffuse. We hypothesize that ntl+ is required for the proper convergence movements of flh-expressing cells.

Animals↗
PubMed1997

Development of branchiomotor neurons in zebrafish.

The mechanisms underlying neuronal specification and axonogenesis in the vertebrate hindbrain are poorly understood. To address these questions, we have employed anatomical methods and mutational analysis to characterize the branchiomotor neurons in the zebrafish embryo. The zebrafish branchiomotor system is similar to those in the chick and mouse, except for the location of the nVII and nIX branchiomotor neurons. Developmental analyses of genes expressed by branchiomotor neurons suggest that the different location of the nVII neurons in the zebrafish may result from cell migration. To gain insight into the mechanisms underlying the organization and axonogenesis of these neurons, we examined the development of the branchiomotor pathways in neuronal mutants. The valentino b337 mutation blocks the formation of rhombomeres 5 and 6, and severely affects the development of the nVII and nIX motor nuclei. The cyclops b16 mutation deletes ventral midline cells in the neural tube, and leads to a severe disruption of most branchiomotor nuclei and axon pathways. These results demonstrate that rhombomere-specific cues and ventral midline cells play important roles in the development of the branchiomotor pathways.

Animals↗