Septate junction proteins are required for cell shape changes, actomyosin reorganization and cell adhesion during dorsal closure in Drosophila.

Septate junctions (SJs) serve as occluding barriers in invertebrate epithelia. In Drosophila, at least 30 genes are required for the formation or maintenance of SJs. Interestingly, loss-of-function mutations in core SJ components are embryonic lethal, with defects in developmental events such as head involution and dorsal closure (DC) that occur prior to the formation of a mature SJ, indicating a role for these proteins in mid-embryogenesis independent of their occluding function. To understand this novel function in development, we examined loss-of-function mutations in three core SJ proteins during the process of DC. DC occurs during mid-embryogenesis to seal a dorsal gap in the epidermis following germ band retraction. Closure is driven by contraction of the extraembryonic amnioserosa cells that temporarily cover the dorsal surface and by cell shape changes (elongation) of lateral epidermal cells that bring the contralateral sheets together at the dorsal midline. Using live imaging and examination of fixed tissues, we show that early events in DC occur normally in SJ mutant embryos, but during later closure, coracle, Macroglobulin complement-related and Neurexin-IV mutant embryos exhibit slower rates of closure and display aberrant cells shapes in the dorsolateral epidermis, including dorsoventral length and apical surface area. SJ mutant embryos also show mild defects in actomyosin structures along the leading edge, but laser cutting experiments suggest similar tension and viscoelastic properties in SJ mutant versus wild type epidermis. In a high percentage of SJ mutant embryos, the epidermis tears free from the amnioserosa near the end of DC and live imaging and immunostaining reveal reduced levels of E-cadherin, suggesting that defective adhesion may be responsible for these tears. Supporting this notion, reducing E-cadherin by half significantly enhances the penetrance of DC defects in coracle mutant embryos.

Expanding the Junction: New Insights into Non-Occluding Roles for Septate Junction Proteins during Development.

The septate junction (SJ) provides an occluding function for epithelial tissues in invertebrate organisms. This ability to seal the paracellular route between cells allows internal tissues to create unique compartments for organ function and endows the epidermis with a barrier function to restrict the passage of pathogens. Over the past twenty-five years, numerous investigators have identified more than 30 proteins that are required for the formation or maintenance of the SJs in Drosophila melanogaster, and have determined many of the steps involved in the biogenesis of the junction. Along the way, it has become clear that SJ proteins are also required for a number of developmental events that occur throughout the life of the organism. Many of these developmental events occur prior to the formation of the occluding junction, suggesting that SJ proteins possess non-occluding functions. In this review, we will describe the composition of SJs, taking note of which proteins are core components of the junction versus resident or accessory proteins, and the steps involved in the biogenesis of the junction. We will then elaborate on the functions that core SJ proteins likely play outside of their role in forming the occluding junction and describe studies that provide some cell biological perspectives that are beginning to provide mechanistic understanding of how these proteins function in developmental contexts.

Marine Derived Anticancer Drugs Targeting Microtubule.

BACKGROUND: Microtubule dynamics plays a vital role in regulating crucial cellular functions and is one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) such as the vinca alkaloids or taxanes, although are effective for cancer therapy, have adverse side effects. Another hindrance in their development is multiple drug resistance in tumor cells. These drawbacks have urged the need to develop novel MTAs from alternative sources, with better therapeutic efficacy. Recently, MTAs from marine sources have grabbed much attention due to unique tubulin binding features and remarkable ability to reduce tumor progression. OBJECTIVE: The emphasis of the article is to provide an overview of some of the most promising marine derived MTAs and highlight their major characteristics in brief. METHOD: Patent databases such as USPTO, Espacenet and WIPO were searched systematically for recent patents published from 2006 up to 2016. Numerous data retrieved was analyzed critically, and only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity are summarized here. RESULTS: Some of the marine derived MTAs have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. CONCLUSION: The marine derived MTAs hold great potential in the field of cancer therapeutics and are gradually advancing in the clinical set up. A deeper understanding of the molecular mechanisms combined with innovative therapeutic regimen would lead to major advances in the field.