Taste receptor cells are responsible for transducing chemical stimuli from the environment and relaying information to the nervous system. Bitter, sweet and umami stimuli utilize G-protein coupled receptors which activate the phospholipase C (PLC) signaling pathway in Type II taste cells. However, it is not known how these cells communicate with the nervous system. Previous studies have shown that the subset of taste cells that expresses the T2R bitter receptors lack voltage-gated Ca2+ channels, which are normally required for synaptic transmission at conventional synapses. Here we use two lines of transgenic mice expressing green fluorescent protein (GFP) from two taste-specific promoters to examine Ca2+ signaling in subsets of Type II cells: T1R3-GFP mice were used to identify sweet- and umami-sensitive taste cells, while TRPM5-GFP mice were used to identify all cells that utilize the PLC signaling pathway for transduction. Voltage-gated Ca2+ currents were assessed with Ca2+ imaging and whole cell recording, while immunocytochemistry was used to detect expression of SNAP-25, a presynaptic SNARE protein that is associated with conventional synapses in taste cells. Depolarization with high K+ resulted in an increase in intracellular Ca2+ in a small subset of non-GFP labeled cells of both transgenic mouse lines. In contrast, no depolarization-evoked Ca2+ responses were observed in GFP-expressing taste cells of either genotype, but GFP-labeled cells responded to the PLC activator m-3M3FBS, suggesting that these cells were viable. Whole cell recording indicated that the GFP-labeled cells of both genotypes had small voltage-dependent Na+ and K+ currents, but no evidence of Ca2+ currents. A subset of non-GFP labeled taste cells exhibited large voltage-dependent Na+ and K+ currents and a high threshold voltage-gated Ca2+ current. Immunocytochemistry indicated that SNAP-25 was expressed in a separate population of taste cells from those expressing T1R3 or TRPM5. These data indicate that G protein-coupled taste receptors and conventional synaptic signaling mechanisms are expressed in separate populations of taste cells. The taste receptor cells responsible for the transduction of bitter, sweet, and umami stimuli are unlikely to communicate with nerve fibers by using conventional chemical synapses.

/pdf/mouse-taste-cells-with-g-protein-coupled-taste-receptors-4jbpg04wka.pdf

Mouse taste cells with G protein-coupled taste receptors lack voltage-gated calcium channels and SNAP-25

Summary
Phagocytosis, the regulated uptake of large particles (>0.5 μm in diameter), is essential for tissue homeostasis and is also an early, critical component of the innate immune response. Phagocytosis can be conceptually divided into three stages: phagosome, formation, maturation, and resolution. Each of these involves multiple reactions that require exquisite spatial and temporal orchestration. The molecular events underlying these stages are being unraveled and the current state of knowledge is briefly summarized in this article.

The life cycle of phagosomes: formation, maturation, and resolution

Understanding brain development remains a major challenge at the heart of understanding what makes us human The neocortex, in evolutionary terms the newest part of the cerebral cortex, is the seat of higher cognitive functions Its normal development requires the production, positioning and appropriate interconnection of very large numbers of both excitatory and inhibitory neurons Pax6 is one of a relatively small group of transcription factors that exert high-level control of cortical development, and whose mutation or deletion from developing embryos causes major brain defects and a wide range of neurodevelopmental disorders Pax6 is very highly conserved between primate and non-primate species, is expressed in a gradient throughout the developing cortex and is essential for normal corticogenesis Our understanding of Pax6’s functions and the cellular processes that it regulates during mammalian cortical development has significantly advanced in the last decade, owing to the combined application of genetic and biochemical analyses Here we review the functional importance of Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of cortical layers and highlight important differences between rodents and primates We also review the pathological effects of PAX6 mutations in human neurodevelopmental disorders Finally, we discuss some aspects of Pax6’s molecular actions including its own complex transcriptional regulation, the distinct molecular functions of its splice variants and some of Pax6’s known direct targets which mediate its actions during cortical development

/pdf/regulation-of-cerebral-cortical-neurogenesis-by-the-pax6-569fltq302.pdf

Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor

The ATP‐binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra‐ and intracellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates and surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly, several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome‐wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole‐exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss‐of‐function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity.

The human ATP‐binding cassette (ABC) transporter superfamily

Pax6 is the universal master control gene for eye morphogenesis. Other than retina and lens, Pax6 also expressed in the ocular surface epithelium from early gestation until the postnatal stage, in which little is known about the function of Pax6. In this study, corneal pannus tissues from patients with ocular surface diseases such as Stevens-Johnson syndrome (SJS), chemical burn, aniridia and recurrent pterygium were investigated. Our results showed that normal ocular surface epithelial cells expressed Pax6. However, corneal pannus epithelial cells from the above patients showed a decline or absence of Pax6 expression, accompanied by a decline or absence of K12 keratin but an increase of K10 keratin and filaggrin expression. Pannus basal epithelial cells maintained nuclear p63 expression and showed activated proliferation, evidenced by positive Ki67 and K16 keratin staining. On 3T3 fibroblast feeder layers, Pax6 immunostaining was negative in clones generated from epithelial cells harvested from corneal pannus from SJS or aniridia, but positive in those from the normal limbal epithelium; whereas western blots showed that some epithelial clones expanded from pannus retained Pax6 expression. Transient transfection of an adenoviral vector carrying EGFP-Pax6 transgenes into these Pax6(-) clones increased both Pax6 and K12 keratin expression. These results indicate that Pax6 helps to maintain the normal corneal epithelial phenotype postnatally, and that down-regulation of Pax6 is associated with abnormal epidermal differentiation in severe ocular surface diseases. Reintroduction of activation of the Pax6 gene might be useful in treating squamous metaplasia of the ocular surface epithelium.

/pdf/down-regulation-of-pax6-is-associated-with-abnormal-1bk6940g7l.pdf

Down-regulation of Pax6 is associated with abnormal differentiation of corneal epithelial cells in severe ocular surface diseases.

PURPOSE. The gene encoding transcription factor Pax6 resides at the top of a genetic hierarchy controlling development and morphogenesis of the eye. Pax6 continues to be expressed in the ocular surface epithelia of the postnatal eye. The goal of this study was to investigate a possible role for Pax6 in controlling dynamics of the ocular surface epithelia. METHODS. Full-length mouse Pax6 (mPax) cDNA, or truncated mPax6286 lacking the transcriptional activation domain was inserted into a tetracycline-inducible vector (Tet-on). A rabbit corneal epithelial cell line SIRC was used to establish stable transformants. Induction of Pax6 or truncated Pax6286 proteins by doxycycline (DOX) was examined by Western blot and immunohistochemistry. The effects of Pax6 overexpression on cell cycle progression were assessed by the cell proliferation index, cell growth curve, and cell cycle assay. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay was performed to detect apoptotic cells. Recombinant adenovirus-carrying mPax6 or mPax6286 transgenes were used for transient transduction of primary rabbit corneal epithelial cells, and the effect on cell cycle progression was assayed. RESULTS. The level of Pax6 or truncated Pax6 was tightly regulated by DOX. Overexpression of full-length Pax6 retarded the rate of cell proliferation, whereas the truncated form had no effect. Full-length Pax6 affected the rate at which individual cells traversed the cell cycle and induced caspase-3-independent apoptosis in a small percentage of cells. Transient transduction of cells with recombinant mPax6 adenovirus also inhibited cell proliferation. CONCLUSIONS. Inhibition of cell proliferation in Pax6-overexpressing corneal epithelial cell lines and primary cell culture is consistent with the notion that Pax6 plays a role in controlling corneal epithelial cell dynamics in vivo. (Invest Ophthalmol Vis Sci. 2006;47:2397–2407) DOI:10.1167/iovs.05-1083

Pax6 overexpression suppresses cell proliferation and retards the cell cycle in corneal epithelial cells.

Intracellular ABCF1 is identified and characterized as a new ligand to extrinsically stimulate retinal pigment epithelial cell phagocytosis. A new approach developed in this study is broadly applicable to many other phagocytes and will enable systematic elucidation of their ligands to broaden understanding of extrinsic regulation and cargo recognition.

ABCF1 extrinsically regulates retinal pigment epithelial cell phagocytosis

Mutations in either tubby or tubby-like protein 1 (Tulp1) cause retinal degeneration with undefined mechanisms. We recently identified both proteins with unconventional secretion as novel MerTK-specific phagocytosis ligands for retinal pigment epithelium (RPE) cells. Using our newly-developed open reading frame (ORF) phage display as a technology for protein-protein interactions, we identified Tulp1 as a Tubby-binding protein. The interaction of tubby and Tulp1 was verified by yeast two-hybrid and protein pull-down assays. Tubby and Tulp1 form heterodimer or heterooligomer and their interaction was functionally revealed by their synergistic stimulation of RPE phagocytosis. Tubby and Tulp1 mediated phagocytosis through MerTK-dependent signaling with non-muscle myosin II redistribution leading to colocalization of phagocytosed vesicles with rearranged NMMIIA.

Synergistic interaction of Tubby and Tubby-like Protein 1 (Tulp1)

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Pax6 overexpression suppresses cell proliferation and retards the cell cycle in corneal epithelial cells.

ABCF1 extrinsically regulates retinal pigment epithelial cell phagocytosis

Synergistic interaction of Tubby and Tubby-like Protein 1 (Tulp1)