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The lacrimal gland (LG) is an exocrine organ responsible for the secretion of aqueous tear film. Regenerative and stem cell therapies that target LG repair are coming to the fore, although our understanding of LG cell lineage hierarchy is still incomplete. We utilize the analysis of label-retaining cells (LRCs) and genetic lineage tracing to define LG cell lineage hierarchy. Our study suggests that embryonic LG contains unique long-lived multipotent stem cells that give rise to all postnatal epithelial cell types. Following birth, lineages become established and the fate of progenitor cell descendants becomes restricted. However, some cell lineages retain plasticity after maturation and can trans-differentiate into other cell types upon injury. The demonstration that the LG contains progenitor cells with different levels of plasticity has profound implications for our understanding of LG gland function in homeostasis and disease and will be helpful for developing stem cell-based therapies in the future.

Pannexins belong to a family of ATP-release channels expressed in almost all cell types. An increasing body of literature on pannexins suggests that these channels play dual and sometimes contradictory roles, contributing to normal cell function, as well as to the pathological progression of disease. In this review, we summarize our understanding of pannexin "protective" and "harmful" functions in inflammation, regeneration and mechanical signaling. We also suggest a possible basis for pannexin's dual roles, related to extracellular ATP and K+ levels and the activation of various types of P2 receptors that are associated with pannexin. Finally, we speculate upon therapeutic strategies related to pannexin using eyes, lacrimal glands, and peripheral nerves as examples of interesting therapeutic targets.

Regeneration is a process that restores structure and function of tissues damaged by injury or disease. In mammals complete regeneration is often unsuccessful, while most of the low phyla animals can re-grow many parts of their body after amputation. Cephalopod molluscs, and in particular Octopus vulgaris, are well known for their capacity to regenerate their arms and other body parts, including central and peripheral nervous system. To better understand the mechanism of recovery following nerve injury in this species we investigated the process of axon regrowth and nerve regeneration after complete transection of the Octopus pallial nerves. This injury induces scar formation and activates the proliferation of hemocytes which invade the lesion site. Hemocytes appear involved in debris removal and seem to produce factors that foster axon re-growth. Connective tissue is involved in driving regenerating fibers in a single direction, outlining for them a well-defined pathway. Injured axons are able to quickly re-grow thus to restoring structure and function.

The pannexin family of channels consists of three members-pannexin-1 (Panx1), pannexin-2 (Panx2), and pannexin-3 (Panx3) that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Pannexin-mediated release of intracellular ATP into the extracellular space has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors. Previous work indicates that the opening of Panx1 channels and activation of purinergic receptors by extracellular ATP may cause inflammation and apoptosis. In the CNS (central nervous system) and PNS (peripheral nervous system), coupled pannexin, and P2 functions have been linked to peripheral sensitization (pain) pathways. Purinergic pathways are also essential for other critical processes in the PNS, including myelination and neurite outgrowth. However, whether such pathways are pannexin-dependent remains to be determined. In this study, we use a Panx1 knockout mouse model and pharmacological inhibitors of the Panx1 and the ATP-mediated signaling pathway to fill gaps in our understanding of Panx1 localization in peripheral nerves, roles for Panx1 in axonal outgrowth and myelination, and neurite extension. Our data show that Panx1 is localized to axonal, myelin, and vascular compartments of the peripheral nerves. Knockout of Panx1 gene significantly increased axonal caliber in vivo and axonal growth rate in cultured dorsal root ganglia (DRG) neurons. Furthermore, genetic knockout of Panx1 or inhibition of components of purinergic signaling, by treatment with probenecid and apyrase, resulted in denser axonal outgrowth from cultured DRG explants compared to untreated wild-types. Our findings suggest that Panx1 regulates axonal growth in the peripheral nervous system.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.08.018 Byline: Irina B. Grishina (a), Sung Yup Kim (a), Christopher Ferrara (a), Helen P. Makarenkova (b), Paul D. Walden (a) Keywords: BMP7; pSmad1; Notch1; Hes1; Prostate; Branching morphogenesis; Urogenital sinus; Epithelium; Mesenchyme Abstract: The mouse prostate gland develops by branching morphogenesis from the urogenital epithelium and mesenchyme. Androgens and developmental factors, including FGF10 and SHH, promote prostate growth (Berman, D.M., Desai, N., Wang, X., Karhadkar, S.S., Reynon, M., Abate-Shen, C., Beachy, P.A., Shen, M.M., 2004. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 267, 387-398; Donjacour, A.A., Thomson, A.A., Cunha, G.R., 2003. FGF-10 plays an essential role in the growth of the fetal prostate. Dev. Biol. 261, 39-54), while BMP4 signaling from the mesenchyme has been shown to suppresses prostate branching (Lamm, M.L., Podlasek, C.A., Barnett, D.H., Lee, J., Clemens, J.Q., Hebner, C.M., Bushman, W., 2001. Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Dev. Biol. 232, 301-314). Here, we show that Bone Morphogenetic Protein 7 (BMP7) restricts branching of the prostate epithelium. BMP7 is expressed in the periurethral urogenital mesenchyme prior to formation of the prostate buds and, subsequently, in the prostate epithelium. We show that BMP7.sup.lacZ/lacZ null prostates show a two-fold increase in prostate branching, while recombinant BMP7 inhibits prostate morphogenesis in organ culture in a concentration-dependent manner. We further explore the mechanisms by which the developmental signals may be interpreted in the urogenital epithelium to regulate branching morphogenesis. We show that Notch1 activity is associated with the formation of the prostate buds, and that Notch1 signaling is derepressed in BMP7 null urogenital epithelium. Based on our studies, we propose a model that BMP7 inhibits branching morphogenesis in the prostate and limits the number of domains with high Notch1/Hes1 activity. Author Affiliation: (a) Department of Urology, New York University School of Medicine, VAMC, 423 East 23rd Street, 18064-South, New York, NY 10010, USA (b) The Neuroscience Institute, 10640 John Jay Hopkins Drive, San Diego, CA 92121, USA Article History: Received 10 June 2004; Revised 11 August 2005; Accepted 11 August 2005

We describe experiments showing that flbroblast growth factor receptor (FGFR) activity is required for early lens development and that there is cooperation with BMP7. The involvement of an FGFR is indicated by the lens development defects that arise in transgenic mice (designated TFR) that express a dominant-negative FGFR1IIIc in the lens lineage from E8.75. Defects include a small lens pit, failure of the lens vesicle to separate from the surface ectoderm, and small lenses subsequently. Cooperation between FGFR and BMP7 signaling during lens development is demonstrated by the exacerbated lens phenotype when. the heterozygous BMP7 condition is added to the TFR transgenics. To define the genetic pathways for lens induction, we have examined the expression level of the lens lineage markers Pax6, FoxE3, and Sox2 in. wild-type mice and in those where BMP7 and/or FGFR signaling is perturbed. Dramatically reduced levels of marker expression suggest a pathway where FGFR and BMP7 signaling converge on Pax6 with FoxE3 positioned downstream. This analysis, when combined with previous experimentation, allows us to define a genetic pathway describing lens induction and development.

FGF-10, a member of the fibroblast growth factor family, is expressed in mesodermally derived cell populations during embryogenesis. During normal ocular development, FGF-10 is expressed in the perioptic mesenchyme adjacent to the Harderian and lacrimal gland primordia. In this report, we provide evidence that FGF-10 is both necessary and sufficient to initiate glandular morphogenesis. Lens-specific expression of FGF-10 was sufficient to induce ectopic ocular glands within the cornea. In addition, lacrimal and Harderian glands were not seen in FGF-10 null fetuses. Based on these results we propose that FGF-10 is an inductive signal that initiates ocular gland morphogenesis. Key Words: FGF-10; cornea; Harderian gland; lacrimal gland; transgenic mice; KGF receptor.

Remodefing of the actin cytoskeleton is a critical early step in skeletal muscle differentiation. Smooth muscle α-actin (SMA) is one of the earliest markers of myoblast differentiation and is important for the migration and cell shape changes that precede fusion. We have found that satellite ceil-derived primary myo- blasts from mice lacking the Barx2 homeobox gene show altered patterns of actin remodeling, reduced cell migration, and delayed differentiation. Consistent with the role of SMA in these processes, Barx2-/- myoblasts also show reduced expression of SMA mRNA and protein. The proximal SMA promoter contains binding sites for muscle regulatory factors and serum response factor as well as a conserved homeodomain binding site (HBS). We found that Barx2 binds to the HBS element and potentiates up-regulation of SMA promoter activity by MyoD. We also show that Barx2, MyoD, and serum response factor simultaneously occupy the SMA promoter in cells and that Barx2 interacts with MyoD. Overall these data indicate that Barx2 cooperates with other muscle-expressed transcription factors to regulate the early cytnskeletal remodeling events that underlie efficient myoblast differentiation. [ABSTRACT FROM AUTHOR]