@article {74, title = {Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Nov}, pages = {1311-20}, abstract = {

MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.

}, keywords = {Animals, Cell Differentiation, Cell Movement, Child, Preschool, Chromosome Breakpoints, Disease Models, Animal, Embryonic Stem Cells, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Genetic Association Studies, Haploinsufficiency, Humans, Intellectual Disability, Mediator Complex, Neural Crest, Neurons, Phenotype, RNA, Messenger, Sequence Analysis, DNA, Transcriptome, Translocation, Genetic, Zebrafish}, issn = {1098-1004}, doi = {10.1002/humu.22636}, author = {Utami, Kagistia Hana and Winata, Cecilia L and Hillmer, Axel M and Aksoy, Irene and Long, Hoang Truong and Liany, Herty and Chew, Elaine G Y and Mathavan, Sinnakaruppan and Tay, Stacey K H and Korzh, Vladimir and Sarda, Pierre and Davila, Sonia and Cacheux, Valere} } @article {72, title = {Wnt signaling is required for early development of zebrafish swimbladder.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e18431}, abstract = {

BACKGROUND: Wnt signaling plays critical roles in mammalian lung development. However, Wnt signaling in the development of the zebrafish swimbladder, which is considered as a counterpart of mammalian lungs, have not been explored. To investigate the potential conservation of signaling events in early development of the lung and swimbladder, we wish to address the question whether Wnt signaling plays a role in swimbladder development.

METHODOLOGY/PRINCIPAL FINDINGS: For analysis of zebrafish swimbladder development, we first identified, by whole-mount in situ hybridization (WISH), has2 as a mesenchymal marker, sox2 as the earliest epithelial marker, as well as hprt1l and elovl1a as the earliest mesothelial markers. We also demonstrated that genes encoding Wnt signaling members Wnt5b, Fz2, Fz7b, Lef1, Tcf3 were expressed in different layers of swimbladder. Then we utilized the heat-shock inducible transgenic lines hs:Dkk1-GFP and hs:ΔTcf-GFP to temporarily block canonical Wnt signaling. Inhibition of canonical Wnt signaling at various time points disturbed precursor cells specification, organization, anterioposterior patterning, and smooth muscle differentiation in all three tissue layers of swimbladder. These observations were also confirmed by using a chemical inhibitor (IWR-1) of Wnt signaling. In addition, we found that Hedgehog (Hh) signaling was activated by canonical Wnt signaling and imposed a negative feedback on the latter.

SIGNIFICANCE/CONCLUSION: We first provided a new set of gene markers for the three tissue layers of swimbladder in zebrafish and demonstrated the expression of several key genes of Wnt signaling pathway in developing swimbladder. Our functional analysis data indicated that Wnt/β-catenin signaling is required for swimbladder early development and we also provided evidence for the crosstalk between Wnt and Hh signaling in early swimbladder development.

}, keywords = {Air Sacs, Animals, Animals, Genetically Modified, Apoptosis, Cell Differentiation, Cell Proliferation, Embryo, Nonmammalian, Epithelium, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Genetic Markers, Green Fluorescent Proteins, Heat-Shock Response, Hedgehog Proteins, Mesoderm, Models, Biological, Morphogenesis, Myocytes, Smooth Muscle, Recombinant Fusion Proteins, Reproducibility of Results, Signal Transduction, Wnt Proteins, Zebrafish, Zebrafish Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0018431}, author = {Yin, Ao and Korzh, Svitlana and Winata, Cecilia L and Korzh, Vladimir and Gong, Zhiyuan} } @article {73, title = {The interaction of epithelial Ihha and mesenchymal Fgf10 in zebrafish esophageal and swimbladder development.}, journal = {Dev Biol}, volume = {359}, year = {2011}, month = {2011 Nov 15}, pages = {262-76}, abstract = {

Developmental patterning and growth of the vertebrate digestive and respiratory tracts requires interactions between the epithelial endoderm and adjacent mesoderm. The esophagus is a specialized structure that connects the digestive and respiratory systems and its normal development is critical for both. Shh signaling from the epithelium regulates related aspects of mammalian and zebrafish digestive organ development and has a prominent effect on esophageal morphogenesis. The mechanisms underlying esophageal malformations, however, are poorly understood. Here, we show that zebrafish Ihha signaling from the epithelium acting in parallel, but independently of Shh, controls epithelial and mesenchymal cell proliferation and differentiation of smooth muscles and neurons in the gut and swimbladder. In zebrafish ihha mutants, the esophageal and swimbladder epithelium is dysmorphic, and expression of fgf10 in adjacent mesenchymal cells is affected. Analysis of the development of the esophagus and swimbladder in fgf10 mutant daedalus (dae) and compound dae/ihha mutants shows that the Ihha-Fgf10 regulatory interaction is realized through a signaling feedback loop between the Ihha-expressing epithelium and Fgf10-expressing mesenchyme. Disruption of this loop further affects the esophageal and swimbladder epithelium in ihha mutants, and Ihha acts in parallel to but independently of Shha in this process. These findings contribute to the understanding of epithelial-mesenchymal interactions and highlight an interaction between Hh and Fgf signaling pathways during esophagus and swimbladder development.

}, keywords = {Air Sacs, Animals, Animals, Genetically Modified, Cell Proliferation, Embryo, Nonmammalian, Epithelium, Esophagus, Female, Fibroblast Growth Factor 10, Gastrointestinal Tract, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Green Fluorescent Proteins, Hedgehog Proteins, In Situ Hybridization, Male, Membrane Proteins, Mesoderm, Microscopy, Confocal, Mutation, Protein Binding, Receptors, Cell Surface, Signal Transduction, Zebrafish, Zebrafish Proteins}, issn = {1095-564X}, doi = {10.1016/j.ydbio.2011.08.024}, author = {Korzh, Svitlana and Winata, Cecilia Lanni and Zheng, Weiling and Yang, Shulan and Yin, Ao and Ingham, Phillip and Korzh, Vladimir and Gong, Zhiyuan} }