The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliferation of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the medaka temperature sensitive mutation eyeless (el) and the zebrafish mutation chokh. In humans, mutations in Rx lead to anophthalmia. All of these studies indicate that Rx genes are key factors in vertebrate eye formation. Because these results cannot be easily reconciled with the most popular dogmas of the field, we offer our interpretation of eye development and evolution.
Development of the visceral mesoderm is a critical process in the organogenesis of the gut. Elucidation of function and regulation of genes involved in the development of visceral mesoderm is therefore essential for an understanding of gut organogenesis. One of the genes specifically expressed in the lateral plate mesoderm, and later in its derivative, the visceral mesoderm, is the Fox gene FoxF1. Its function is critical for Xenopus gut development, and embryos injected with FoxF1morpholino display abnormal gut development. In the absence of FoxF1function, the lateral plate mesoderm, and later the visceral mesoderm, does not proliferate and differentiate properly. Region- and stage-specific markers of visceral mesoderm differentiation, such as Xbap and α-smooth muscle actin, are not activated. The gut does not elongate and coil. These experiments provide support for the function of FoxF1 in the development of visceral mesoderm and the organogenesis of the gut. At the molecular level, FoxF1 is a downstream target of BMP4 signaling. BMP4 can activate FoxF1 transcription in animal caps and overexpression of FoxF1 can rescue twinning phenotypes, which results from the elimination of BMP4 signaling. The cis-regulatory elements of FoxF1are located within a 2 kb DNA fragment upstream of the coding region. These sequences can drive correct temporal-spatial expression of a GFP reporter gene in transgenic Xenopus tadpoles. These sequences represent a unique tool, which can be used to specifically alter gene expression in the lateral plate mesoderm.
Rx is a paired-like homeobox gene that is required for vertebrate eye formation. Mice lacking Rx function do not develop eyes or the posterior pituitary. To determine whether Rx is required cell autonomously in these tissues, we generated embryonic chimeras consisting of wild type and Rx−/− cells. We found that in the eye, Rx-deficient cells cannot participate in the formation of the neuroretina, retina pigment epithelium and the distal part of the optic stalk. In addition, in the ventral forebrain, Rx function is required cell autonomously for the formation of the posterior pituitary. Interestingly, Rx−/− and wild type cells segregate before the morphogenesis of these two tissues begins. Our observations suggest that Rx function is not only required for the morphogenesis of the retina and posterior pituitary, but also prior to morphogenesis, for the sorting out of cells to form distinct fields of retinal/pituitary cells.
The complement system is the central component of innate immunity and an important player in the adaptive immunity of vertebrates. We analyzed the expression patterns of several key members of the complement cascade during Xenopus development. We found extensive expression of these molecules already during gastrula/early neurula stage. Remarkably, several genes also showed an organ-specific expression pattern during early organogenesis. Early expression is notable for two different expression patterns in the neuroectoderm. In one group, there is early strong neural plate and neural precursor expression. This is the case of properdin, C1qA, C3 and C9. The second pattern, seen with C1qR and C6, is noteworthy for its expression at the periphery of the neural plate, in the presumptive neural crest. Two genes stand out for their predominantly mesodermal expression. C3aR, the message for the cognate receptor for C3 in the complement cascade, is expressed at the same time as C3, but in a complementary, reciprocal pattern in the mesoderm. C1qA expression also predominates in somites, pronephros, visceral mesoderm and ventral blood islands. Finally, several genes are characterized by later expression in developing organs. C1qR displays a reticular pattern consistent with expression in the developing vasculature. The late expression of C1qA and C3bC4b is strongest in the pronephros. Finally, the expression of properdin in the hindbrain and in the developing lens are novel findings. The expression patterns of these molecules suggest that these components of the complement system may have in Xenopus a so far undefined developmental role.
The majority of human skeletal dysplasias are caused by dysregulation of growth plate homeostasis. As TGF-β signaling is a critical determinant of growth plate homeostasis, skeletal dysplasias are often associated with dysregulation of this pathway. The context-dependent action of TFG-β signaling is tightly controlled by numerous mechanisms at the extracellular level and downstream of ligand-receptor interactions. However, TGF-β is synthesized as an inactive precursor that is cleaved to become mature in the Golgi apparatus, and the regulation of this posttranslational intracellular processing and trafficking is much less defined. Here, we report that a cysteine-rich protein, E-selectin ligand-1 (ESL-1), acts as a negative regulator of TGF-β production by binding TGF-β precursors in the Golgi apparatus in a cell-autonomous fashion, inhibiting their maturation. Furthermore, ESL-1 inhibited the processing of proTGF-β by a furin-like protease, leading to reduced secretion of mature TGF-β by primary mouse chondrocytes and HEK293 cells. In vivo loss of Esl1 in mice led to increased TGF-β/SMAD signaling in the growth plate that was associated with reduced chondrocyte proliferation and delayed terminal differentiation. Gain-of-function and rescue studies of the Xenopus ESL-1 ortholog in the context of early embryogenesis showed that this regulation of TGF-β/Nodal signaling was evolutionarily conserved. This study identifies what we believe to be a novel intracellular mechanism for regulating TGF-β during skeletal development and homeostasis.
The transcription factor Pitx3 is critical for lens formation. Deletions in the promoter of this gene cause abnormal lens development in the aphakia (ak) mouse mutant, which has only rudimentary lenses. In this study, we investigated the role of Pitx3 in lens development and differentiation. We found that reduced expression of Pitx3 leads to changes in the proliferation, differentiation and survival of lens cells. The genetic interactions between Pitx3 and Foxe3 were investigated, as these two transcription factors are expressed at the same time in lens development and their absence has similar consequences for lens development. We found no evidence that these two genes genetically interact. In general, our study shows that the abnormal phenotype of the ak lenses is not due to just one molecular pathway, rather in the absence of Pitx3 expression multiple aspects of lens development are disrupted. Developmental Dynamics 238: 2193-2201, 2009.
In this article we report the isolation of a novel zebrafish gene, pitx3, which plays an important role in the formation of several placode-derived structures. In wildtype embryos, pitx3 is first expressed in a crescent-shaped area in the anterior end of the embryo. At later stages, the primordia of the anterior pituitary, the lens, the olfactory sensory epithelium, and cranial ganglia express this gene. Pitx3 is not expressed in the more posterior preplacodal region that gives rise to the epibranchial, otic, and lateral line placodes. The dynamics of pitx3 in the anterior region of wildtype embryos suggests that pitx3 expression marks a common step in the formation of the pituitary, lens, olfactory placode as well as the trigeminal placode. Analysis of pitx3 expression in mutants lacking the hedgehog or nodal function demonstrates the differential dependence of pitx3 expression in these structures on nodal and hedgehog signaling. While the lens and trigeminal placodes express pitx3 in the absence of hedgehog and nodal signaling, there is no expression of pitx3 in the anteriormost ectoderm adjacent to the neural plate from which the anterior pituitary would derive. In mutants with impaired hedgehog signaling, the lens placode frequently extends into more anterior ventral regions of the embryo.
Fox (forkhead) genes encode transcription factors that play important roles in the regulation of embryonic patterning as well as in tissue specific gene expression. Mutations in the human FOXP2 gene cause abnormal speech development. Here we report the structure and expression pattern of zebrafish FoxP2. In zebrafish, this gene is first expressed at the 20-somite stage in the presumptive telencephalon. At this stage there is a significant overlap of FoxP2 expression with the expression of the emx homeobox genes. However, in contrast to emx1, FoxP2 is not expressed in the pineal gland or in the pronephric duct. After 72 hours of development, the expression of zebrafish FoxP2 becomes more complex in the brain. The developing optic tectum becomes the major area of FoxP2 expression. In the adult brain, the highest concentrations of the FoxP2 transcript can be observed in the optic tectum. In the cerebellum, only the caudal lobes show high levels of Foxp2 expression. These regions correspond to the vestibulocerebellum of mammals. Several other regions of the brain also show high levels of Foxp2 expression. KEY WORDS: Emx, forkhead, FoxP2, homeobox, speech, telencephalon, zebrafish Forkhead proteins are important transcriptional regulators that are involved in pattern formation during vertebrate development as well as in tissue specific gene expression and tumorogenesis (Accili and Arden, 2004, Carlsson and Mahlapuu, 2002, Dirksen and Jamrich, 1992, Dirksen and Jamrich, 1995, El-Hodiri et al., 2001, Erickson, 2001, Kaufmann and Knochel, 1996, Lai et al., 2001, Lai et al., 1990, Lehmann et al., 2003, Li and Vogt, 1993, Tseng et al., 2004.FOXP2, a member of the Foxp subfamily of Fox genes, is the only gene shown to be involved in speech and language development in humans (Bruce and Margolis, 2002, Enard et al., 2002, Fisher et al., 1998, Katoh, 2004, Lai et al., 2001, Lu et al., 2002, Saleem et al., 2003, Shu et al., 2001, Wang et al., 2003, Zhang et al., 2002. Mutations in this gene result in impaired linguistic and grammatical skills that, together with diminished control of complex face and mouth movements, lead to disrupted speech (Hurst et al., 1990. A recent study showed expression of FoxP2 in the entire adult brain of birds and crocodiles (Haesler et al., 2004). In this paper, we provide information about the isolation, sequence and expression pattern of zebrafish FoxP2 during development and in adult brain.Foxp2 is somewhat of an unusual protein in that it contains Int. J. Dev. Biol. 50: 435-438 (2006) a forkhead and zinc finger domain. PCR and degenerate primers were used to isolate a cDNA fragment of the zebrafish FoxP2 gene that encodes both of these domains of the protein.After sequencing the isolated PCR fragment, we found that our sequence has a high homology to several zebrafish EST fragments in the GenBank database. Figure 1 shows the comparison of the deduced amino acid sequence of the zebrafish to the mouse and human FOXP2 protein. This comparison shows that the FoxP2 protein is highly ...
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