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1.  Sensory Neuron Differentiation is Regulated by Notch Signaling in the Trigeminal Placode 
Developmental biology  2010;344(2):836-848.
Trigeminal sensory neurons develop from the neural crest and neurogenic placodes, and have been studied as a principle model of sensory neuron formation. While the Notch pathway has been extensively characterized in central nervous system development and other developmental processes, it has not been well characterized in sensory neurogenesis. Here we studied the functional role of Notch signaling in the trigeminal ophthalmic (opV) placode, a prime model of sensory neurogenesis. To establish a good spatiotemporal description of Notch pathway genes in the chick trigeminal placode, a stage-specific expression analysis was conducted, showing that expression of most Notch pathway genes and effectors are expressed in the placode, with expression primarily being confined to ectodermal cells. Expression was highest at stages of peak neuronal differentiation. To test the function of Notch signaling in opV placode cell differentiation, Notch receptor cleavage was blocked using the gamma-secretase inhibitor, DAPT, or signaling was activated by misexpression of the Notch intracellular domain (NICD). Notch activation resulted in a significant reduction in sensory neurogenesis. Cells remained in the ectoderm and did not differentiate. Expression of the opV specification marker Pax3 was also lost in targeted cells. DAPT exposure resulted in a dramatic increase in neurogenesis without increasing proliferation, where many differentiated cells were found in the mesenchyme and, surprisingly, within the ectoderm. This is the first result clearly showing prolific neuronal differentiation in the ectoderm of the trigeminal placodes after experimental manipulation of a molecular signaling pathway, thus identifying Notch signaling as a primary regulator of the sensory neuron fate in the opV placode.
doi:10.1016/j.ydbio.2010.05.514
PMCID: PMC3911820  PMID: 20537991
Sensory neurogenesis; Notch; Trigeminal ophthalmic placode
2.  Structural Variations in Articular Cartilage Matrix Are Associated with Early-Onset Osteoarthritis in the Spondyloepiphyseal Dysplasia Congenita (Sedc) Mouse 
Heterozgyous spondyloepiphyseal dysplasia congenita (sedc/+) mice expressing a missense mutation in col2a1 exhibit a normal skeletal morphology but early-onset osteoarthritis (OA). We have recently examined knee articular cartilage obtained from homozygous (sedc/sedc) mice, which express a Stickler-like phenotype including dwarfism. We examined sedc/sedc mice at various levels to better understand the mechanistic process resulting in OA. Mutant sedc/sedc, and control (+/+) cartilages were compared at two, six and nine months of age. Tissues were fixed, decalcified, processed to paraffin sections, and stained with hematoxylin/eosin and safranin O/fast green. Samples were analyzed under the light microscope and the modified Mankin and OARSI scoring system was used to quantify the OA-like changes. Knees were stained with 1C10 antibody to detect the presence and distribution of type II collagen. Electron microscopy was used to study chondrocyte morphology and collagen fibril diameter. Compared with controls, mutant articular cartilage displayed decreased fibril diameter concomitant with increases in size of the pericellular space, Mankin and OARSI scores, cartilage thickness, chondrocyte clustering, proteoglycan staining and horizontal fissuring. In conclusion, homozygous sedc mice are subject to early-onset knee OA. We conclude that collagen in the mutant’s articular cartilage (both heterozygote and homozygote) fails to provide the normal meshwork required for matrix integrity and overall cartilage stability.
doi:10.3390/ijms140816515
PMCID: PMC3759923  PMID: 23939426
spondyloepiphyseal dysplasia congenita (sedc); proteoglycan; animal model of osteoarthritis; Col2a1; type II collagen; articular cartilage; extracellular matrix
3.  The expression patterns of minor fibrillar collagens during development in zebrafish 
Gene expression patterns : GEP  2010;10(7-8):315-322.
Minor fibrillar collagens are recognized as the organizers and nucleators during collagen fibrillogenesis but likely serve additional functions. The minor fibrillar collagens include collagens type V and type XI. Mutations of collagen type V and XI can cause Ehlers Danlos, Stickler’s, and Marshall’s syndromes in human. We have characterized the spatiotemporal expression patterns of Col11a1, Col11a2, Col5a1 as well as Col5a3 in zebrafish embryos by in situ hybridization. Col5a1 is expressed in developing somites, neural crest, the head mesenchyme, developing cranial cartilage, pharyngeal arches and vertebrae. Col5a3 is detected in the notochord, mesenchyme cells in the eyes and lens. Both Col11a1 and Col11a2 have similar expression patterns, including notochord, otic vesicle, and developing cranial cartilages. Zebrafish may therefore serve as a valuable vertebrate model system for the study of diseases associated with collagens type V and XI mutations.
doi:10.1016/j.gep.2010.07.002
PMCID: PMC2956583  PMID: 20647059
minor fibrillar collagens; zebrafish; development; in situ hybridization; Danio rerio
4.  Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice 
Nature immunology  2005;7(1):83-92.
The in vivo mechanism of regulatory T cell (Treg cell) function in controlling autoimmunity remains controversial. Here we have used two-photon laser-scanning microscopy to analyze lymph node priming of diabetogenic T cells and to delineate the mechanisms of Treg cell control of autoimmunity in vivo. Islet antigen–specific CD4+CD25− T helper cells (TH cells) and Treg cells swarmed and arrested in the presence of autoantigens. These TH cell activities were progressively inhibited in the presence of increasing numbers of Treg cells. There were no detectable stable associations between Treg and TH cells during active suppression. In contrast, Treg cells directly interacted with dendritic cells bearing islet antigen. Such persistent Treg cell–dendritic cell contacts preceded the inhibition of TH cell activation by dendritic cells, supporting the idea that dendritic cells are central to Treg cell function in vivo.
doi:10.1038/ni1289
PMCID: PMC3057888  PMID: 16311599
5.  Central role of a defective interleukin-2 production in triggering islet autoimmune destruction 
Immunity  2008;28(5):687-697.
Summary
The dynamics of CD4+ effector T (Teff)cells and CD4+Foxp3+ regulatory T (Treg)cells during diabetes progression in non-obese diabetic mice was investigated to determine if an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg:Teff ratio in inflamed islets, but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2 suggesting that their decline was due to increased apoptosis. Additionally, administration of low dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and development of diabetes in the non-obese diabetic mice.
doi:10.1016/j.immuni.2008.03.016
PMCID: PMC2394854  PMID: 18468463

Results 1-5 (5)