Ivermectin Enhances Paclitaxel Efficacy by Overcoming Resistance Through Modulation of in Non-small Cell Lung Cancer.

Background/aim: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells.

Inter-subspecies mouse F1 hybrid embryonic stem cell lines newly established for studies of allelic imbalance in gene expression.

Allele-specific monoallelic gene expression is a unique phenomenon and a great resource for analyzing gene regulation. To study this phenomenon, we established new embryonic stem (ES) cell lines derived from F1 hybrid blastocysts from crosses between four mouse subspecies (Mus musculus domesticus, C57BL/6; M. musculus molossinus, MSM/Ms; M.

The shh limb enhancer is activated in patterned limb regeneration but not in hypomorphic limb regeneration in Xenopus laevis.

Xenopus young tadpoles regenerate a limb with the anteroposterior (AP) pattern, but metamorphosed froglets regenerate a hypomorphic limb after amputation. The key gene for AP patterning, shh, is expressed in a regenerating limb of the tadpole but not in that of the froglet. Genomic DNA in the shh limb-specific enhancer, MFCS1 (ZRS), is hypermethylated in froglets but hypomethylated in tadpoles: shh expression may be controlled by epigenetic regulation of MFCS1.

Gene regulatory landscape of the sonic hedgehog locus in embryonic development.

The organs of vertebrate species display a wide variety of morphology. A remaining challenge in evolutionary developmental biology is to elucidate how vertebrate lineages acquire distinct morphological features. Developmental programs are driven by spatiotemporal regulation of gene expression controlled by hundreds of thousands of cis-regulatory elements.

Temporospatial sonic hedgehog signalling is essential for neural crest-dependent patterning of the intrinsic tongue musculature.

The tongue is a highly specialised muscular organ with a complex anatomy required for normal function. We have utilised multiple genetic approaches to investigate local temporospatial requirements for sonic hedgehog (SHH) signalling during tongue development. Mice lacking a -enhancer, (), with reduced SHH in dorsal tongue epithelium have perturbed lingual septum tendon formation and disrupted intrinsic muscle patterning, with these defects reproduced following global deletion from E10.

SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization.

Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, regulation in the PrCP is crucial for initiation of forebrain development.

N-Acyldopamine induces aggresome formation without proteasome inhibition and enhances protein aggregation via p62/SQSTM1 expression.

Accumulation of ubiquitinated protein aggregates is a common pathology associated with a number of neurodegenerative diseases and selective autophagy plays a critical role in their elimination. Although aging-related decreases in protein degradation properties may enhance protein aggregation, it remains unclear whether proteasome dysfunction is indispensable for ubiquitinated-protein aggregation in neurodegenerative diseases. Here, we show that N-oleoyl-dopamine and N-arachidonyl-dopamine, which are endogenous brain substances and belong to the N-acyldopamine (AcylDA) family, generate cellular inclusions through aggresome formation without proteasome inhibition.

Enhancer adoption caused by genomic insertion elicits interdigital expression and syndactyly in mouse.

Acquisition of new -regulatory elements (CREs) can cause alteration of developmental gene regulation and may introduce morphological novelty in evolution. Although structural variation in the genome generated by chromosomal rearrangement is one possible source of new CREs, only a few examples are known, except for cases of retrotransposition. In this study, we show the acquisition of novel regulatory sequences as a result of large genomic insertion in the spontaneous mouse mutation Hammer toe ().

SHH signaling directed by two oral epithelium-specific enhancers controls tooth and oral development.

Interaction between the epithelium and mesenchyme coordinates patterning and differentiation of oral cavity structures including teeth, palatal rugae and tongue papillae. SHH is one of the key signaling molecules for this interaction. Epithelial expression of Shh in the tooth buds and tongue papillae is regulated by at least two enhancers, MRCS1 and MFCS4.

Two Types of Etiological Mutation in the Limb-Specific Enhancer of .

An enhancer named MFCS1 regulates Sonic hedgehog () expression in the posterior mesenchyme of limb buds. Several mutations in MFCS1 induce ectopic expression in the anterior limb bud, and these result in preaxial polydactyly (PPD). However, the molecular basis of ectopic expression remains elusive, although some mutations are known to disrupt the negative regulation of expression in the anterior limb bud.

Evolution of Shh endoderm enhancers during morphological transition from ventral lungs to dorsal gas bladder.

Shh signalling plays a crucial role for endoderm development. A Shh endoderm enhancer, MACS1, is well conserved across terrestrial animals with lungs. Here, we first show that eliminating mouse MACS1 causes severe defects in laryngeal development, indicating that MACS1-directed Shh signalling is indispensable for respiratory organogenesis.

The Hand2 gene dosage effect in developmental defects and human congenital disorders.

Heart- and neural crest derivatives-expressed (Hand) proteins belong to the Twist family of the basic helix-loop-helix (bHLH) transcription factors, and play crucial roles in the development of several organs. They form heterodimers with Twist1 via their HLH domain. Disruption of the expression balance between Hand2 and Twist1 causes limb malformation, indicating that the expression level of Hand2 relative to Twist1 is essential for limb development.

A novel regulatory element for Shh expression in the lung and gut of mouse embryos.

Hedgehog (Hh) signaling plays pivotal roles in morphogenesis of several embryonic tissues, including the primitive gut. In the mouse embryo, Sonic hedgehog (Shh) is expressed in endodermal epithelia from the oral cavity to the intestine, and contributes to cell proliferation in the underlying mesenchyme and subsequent differentiation into the gastrointestinal smooth muscle. Three evolutionary conserved non-coding sequences in the region upstream of the Shh coding sequence contain endoderm-specific enhancers for Shh expression.

Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q.

Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown.

Prx-1 expression in Xenopus laevis scarless skin-wound healing and its resemblance to epimorphic regeneration.

Despite a strong clinical need for inducing scarless wound healing, the molecular factors required to accomplish it are unknown. Although skin-wound healing in adult mammals often results in scarring, some amphibians can regenerate injured body parts, even an amputated limb, without it. To understand the mechanisms of perfect skin-wound healing in regenerative tetrapods, we studied the healing process in young adult Xenopus "froglets" after experimental skin excision.

Anterior shift in gene expression precedes anteriormost digit formation in amniote limbs.

In tetrapod limbs, an anteriormost digit has common traits of small, short and less-phalange morphology. In this study, we focused on three genes, Mkp3, Sef and Tsukushi (TSK), which have anterior-specific or anterior-prominent expression patterns in the developing limb bud at the autopod-forming stage. The anterior expression is not fixed in the period of limb development, but the expression domains of Mkp3, Sef and TSK change considerably from the distal domain to the anterior domain.

Essential mesenchymal role of small GTPase Rac1 in interdigital programmed cell death during limb development.

Developing vertebrate limbs are often utilized as a model for studying pattern formation and morphogenetic cell death. Herein, we report that conditional deletion of Rac1, a member of the Rho family of proteins, in mouse limb bud mesenchyme led to skeletal deformities in the autopod and soft tissue syndactyly, with the latter caused by a complete absence of interdigital programmed cell death. Furthermore, the lack of interdigital programmed cell death and associated syndactyly was related to down-regulated gene expression of Bmp2, Bmp7, Msx1, and Msx2, which are known to promote apoptosis in the interdigital mesenchyme.

A cluster of three long-range enhancers directs regional Shh expression in the epithelial linings.

The sonic hedgehog (Shh) pathway plays indispensable roles in the morphogenesis of mouse epithelial linings of the oral cavity and respiratory and digestive tubes. However, no enhancers that regulate regional Shh expression within the epithelial linings have been identified so far. In this study, comparison of genomic sequences across mammalian species and teleost fishes revealed three novel conserved non-coding sequences (CNCSs) that cluster in a region 600 to 900 kb upstream of the transcriptional start site of the mouse Shh gene.

Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription.

The expression of Sonic hedgehog (Shh) in mouse limb buds is regulated by a long-range enhancer 1 Mb upstream of the Shh promoter. We used 3D-FISH and chromosome conformation capture assays to track changes at the Shh locus and found that long-range promoter-enhancer interactions are specific to limb bud tissues competent to express Shh. However, the Shh locus loops out from its chromosome territory only in the posterior limb bud (zone of polarizing activity or ZPA), where Shh expression is active.

Joint development in Xenopus laevis and induction of segmentations in regenerating froglet limb (spike).

In Xenopus laevis, amputation of the adult limb results in the formation of a simple (hypomorphic) spike-like structure without joints, although tadpole limb bud regenerates complete limb pattern. The expression of some joint marker genes was examined in limb development and regeneration. Bmp-4 and gdf-5 were expressed and sox-9 expression was decreased in the joint region.

Region-specific expression of mario reveals pivotal function of the anterior nondigit region on digit formation in chick wing bud.

We report the region-specific expression of a novel gene, named mario, whose expression domain is in the distal tip of the presumptive and developing digit 2 region in the developing chick wing bud. The anterior region-specific expression of mario corresponds well with the presence of digit 2, and fate map analysis showed that mario expression at early stages represents the presumptive digit 2 region. Using mario expression as a region-specific marker for the digit 2 region, several surgical operations were performed to obtain insights into digit 2 development in the chick wing.

Expression of rigf, a member of avian VEGF family, correlates with vascular patterning in the developing chick limb bud.

In a differential display screening for genes regulated by retinoic acid in the developing chick limb bud, we have isolated a novel gene, termed rigf, retinoic-acid induced growth factor, that encodes a protein belonging to the vascular endothelial growth factor (VEGF) family. Rigf transcripts were found in the posterior region of the limb bud in a region-specific manner as well as in other embryonic tissues and regions, including the notochord, head and trunk mesenchyme, retinal pigment epithelium, and branchial arches. Several manipulations revealed that retinoic acid and sonic hedgehog signaling pathways regulate rigf expression in the limb bud.