Search

To improve cancer disparities among under-represented minority (URM) populations, better representation of URM individuals in cancer research is needed. The San Diego State University and University of California San Diego Moores Cancer Center Partnership is addressing cancer disparities through an educational program targeting undergraduate URM students. The Partnership provides a paid intensive summer research internship enriched with year-round activities that include educational sessions, a journal club, mentorship, social activities, and poster sessions and presentations. Program evaluation through follow-up surveys, focus groups, and other formal and informal feedback, including advisory and program steering committees, are used to improve the program. Long-term follow-up among scholars (minimum of 10 years) provides data to evaluate the program's long-term impact on scholars' education and career path. Since 2016, 63 URM undergraduate students participated in the scholar program. At the year-2 follow-up (2016 cohort; n = 12), 50% had completed their Graduate Record Examination (GRE) and/or applied to graduate or medical school. Lessons learned during the course of the program led to implementation of changes to provide a better learning experience and increase overall program satisfaction. Updates were made to recruitment timeline, improvements of the recruitment processes, refinement of the program contracts and onboarding meetings, identification of essential program coordinator skills and responsibilities, adjustments to program components, and establishment of a well-mapped and scheduled evaluation plan. The Partnership identified best practices and lessons learned for implementing lab-based internship scholar programs in biomedical and public health fields that could be considered in other programs.

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis.

Byline: Kathryn M. Ryan, Jill D. Hendren, Lynda A. Helander, Richard M. Cripps Keywords: Heart; Inflow tract; Seven-up; COUP-TF; Tinman; NKX2.5; Transcriptional regulation Abstract: A complex regulatory cascade is required for normal cardiac development, and many aspects of this network are conserved from Drosophila to mammals. In Drosophila, the seven-up (svp) gene, an ortholog of the vertebrate chick ovalbumin upstream promoter transcription factors (COUP-TFI and II), is initially activated in the cardiac mesoderm and is subsequently restricted to cells forming the cardiac inflow tracts. Here, we investigate svp regulation in the developing cardiac tube. Using bioinformatics, we identify a 1007-bp enhancer of svp which recapitulates its entire expression in the embryonic heart and other mesodermal derivatives, and we show that this enhancer is initially activated by the NK homeodomain factor Tinman (Tin) via two conserved Tin binding sites. Mutation of the Tin binding sites significantly reduces enhancer activity both during normal development and in response to ectopic Tin. This is the first identification of an enhancer for the complex svp gene, demonstrating the effectiveness of bioinformatics tools in assisting in unraveling transcriptional regulatory networks. Our studies define a critical component of the svp regulatory cascade and place gene regulatory events in direct apposition to the formation of critical cardiac structures. Author Affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA Article History: Received 1 August 2006; Revised 20 September 2006; Accepted 14 October 2006

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.09.007 Byline: TyAnna L. Lovato, Adrian R. Benjamin, Richard M. Cripps Keywords: Mef2; Twist; Drosophila; Ecdysone; Steroid hormone; Broad Complex; Muscle differentiation Abstract: The steroid hormone 20-hydroxyecdysone (ecdysone) activates a relatively small number of immediate-early genes during Drosophila pupal development, yet is able to orchestrate distinct differentiation events in a wide variety of tissues. Here, we demonstrate that expression of the muscle differentiation gene Myocyte enhancer factor-2 (Mef2) is normally delayed in twist-expressing adult myoblasts until the end of the third larval instar. The late up-regulation of Mef2 transcription in larval myoblasts is an ecdysone-dependent event which acts upon an identified Mef2 enhancer, and we identify enhancer sequences required for up-regulation. We also present evidence that the ecdysone-induced Broad Complex of zinc finger transcription factor genes is required for full activation of the myogenic program in these cells. Since forced early expression of Mef2 in adult myoblasts leads to premature muscle differentiation, our results explain how and why the adult muscle differentiation program is attenuated prior to pupal development. We propose a mechanism for the initiation of adult myogenesis, whereby twist expression in myoblasts provides a cellular context upon which an extrinsic signal builds to control muscle-specific differentiation events, and we discuss the general relevance of this model for gene regulation in animals. Author Affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131-1091, USA Article History: Received 2 July 2005; Revised 2 September 2005; Accepted 2 September 2005

Myocyte enhancer factor-2 (MEF2) is a transcription factor that is necessary for embryonic muscle developmerit in Drosophila and vertebrates; however, whether this factor is required during later muscle development remains largely unknown. Using heteroallelic combinations of different Mef2 mutant alleles, we isolated and characterized a temperature-sensitive combination. Through temperature-shift experiments, we obtained adult animals that were lacking proper MEF2 function. Many of these individuals died as mature pupae, and those that eclosed showed poor locomotion and an inability to fly. Histological analysis of these animals revealed a requirement for MEF2 in skeletal muscle patterning, although these animals had strikingly normal amounts of muscle tissue. Using quantitative polymerase chain reaction, we determined that expression of the MEF2-regulated actin gene Act57B was severely reduced in these animals. By contrast myofibrillar actin genes unique to the adult stage were only mildly affected. Since MEF2 mutant adults were still capable of forming muscle tissue, we conclude that MEF2 is required for the expression of only a subset of muscle structural genes in the adult. These results indicate that additional muscle-specific factors function to control the myogenesis of complex and diverse muscle in the adult.

The myocyte enhancer factor-2 (MEF2) transcription factor plays a central role in the activation and maintenance of muscle gene expression in fruit flies and vertebrates. The mechanism of action and downstream target genes of MEF2 have been defined in considerable detail, but relatively little is known about the mechanisms that regulate MEF2 expression during muscle development. Here we demonstrate that MEF2 maintains its own expression in all differentiated muscle cell types during late embryonic and larval development in Drosophila by binding a conserved MEF2 site in a muscle-specific regulatory enhancer. Ectopic expression of Mef2 is sufficient to directly activate this enhancer in some, but not all, non-muscle cells. Furthermore, activation of the Mef2 enhancer normally in muscle cells and ectopically in non-muscle cells is dependent upon the integrity of the MEF2 binding site. These findings suggest an evolutionarily conserved mechanism whereby MEF2 can stabilize the muscle phenotype by sustaining its own expression through a myogenic autoregulatory loop. Keywords: Myocyte enhancer factor-2; Muscle; Mesoderm; Transcription; Autoregulation; Enhancer; Drosophila; Evolutionary conservation

Members of the basic helix-loop-helix (bHLH) transcription factor family play an essential role in multiple developmental processes. During neurogenesis, positive and negative regulation by bHLH proteins is essential for proper development. Here we report the identification and initial characterization of the bHLH gene, Neuronal twist (N-twist), named for its neural expression pattern and high sequence homology and physical linkage to the mesodermal inhibitor, M-twist. N-twist is expressed in the developing mouse central nervous system in the midbrain, hindbrain, and neural tube. This neural expression is conserved in invertebrates, as expression of the Drosophila ortholog of N-twist is also restricted to the central nervous system. Like other bHLH family members, N-Twist heterodimerizes with E protein and binds DNA at a consensus bHLH-binding site, the E box. We show that N-Twist inhibits MASH1-dependent transcriptional activation by sequestering E protein in a dominant negative fashion. Thus, these studies support the notion that N-Twist represents a novel negative regulator of neurogenesis. Key Words: N-twist; basic-helix-loop-helix; bHLH; achaete-scute; neurogenesis; MASH1; inhibitor; transcription; brain; neural tube; mouse; Drosophila.

Formation of the heart is dependent on an intricate cascade of developmental decisions. Analysis of the molecules and mechanisms involved in the specification of cardiac cell fates, differentiation and diversification of cardiac muscle cells, and morphogenesis and patterning of different cardiac cell types has revealed an evolutionarily conserved network of signaling pathways and transcription factors that underlies these processes. The regulatory network that controls the formation of the primitive heart in fruit flies has been elaborated upon to form the complex multichambered heart of mammals. We compare and contrast the mechanisms involved in heart formation in fruit flies and mammals in the context of a network of transcriptional interactions and point to unresolved questions for the future. Key Words: heart; cardiogenesis; dorsal vessel; Drosophila; review; gene network; transcription factor; transcription network.

The MADS-box transcription factor MEF2 is expressed specifically in developing cardiac, somatic, and visceral muscle cell lineages during Drosophila embryogenesis and is required for myoblast differentiation and muscle morphogenesis. To define the mechanisms that regulate Mef2 transcription, we have analyzed the Mef2 upstream region for sequences sufficient to recapitulate the expression pattern of the gene in Drosophila embryos. Here we describe a complex enhancer located 5.8 kb upstream of the Drosophila Mef2 gene that controls transcription in cardial cells of the dorsal vessel, a subset of somatic muscle founder cells, and the visceral muscle cells. The core of this enhancer contains two evolutionarily conserved binding sites for the homeodomain protein Tinman (Tin), expressed in developing cardiac, somatic, and visceral muscle lineages. Both Tin binding sites are required for enhancer activity in all three muscle cell lineages. Whereas the 285-bp enhancer core alone is sufficient for expression in cardiac cells, expression in somatic founder cells and visceral muscle is dependent on the core enhancer plus unique flanking sequences that include an evolutionarily conserved E box. These results reveal an essential role for Tin in activation of Mef2 transcription in multiple myogenic lineages and demonstrate that transcriptional activity of Tin is dependent on combinatorial interactions with other factors unique to different muscle cell types.

Mef2, the myogenic regulatory gene, is a direct target for transcriptional activation by Twist, the bHLH transcription factor, during myogenesis in Drosophila. Twist controls Mef2 expression directly in adult somatic muscle precursor cells through a 175-bp enhancer 2245 bp upstream from the transcription start site. A novel transcription pathway has been defined for skeletal muscle development.

Twenty-two autosomal dominant flightless mutations are identified to study the muscle function affecting mutations in Drosophila melanogaster. Seven functional alleles of indirect flight muscle-specific Act88F actin gene and eight viable alleles of muscle myosin heavy chain (MhC) gene are present in the mutant area. Mhc and Act88F mutations exhibit diverse phenotypic characteristics. The five lethal alleles, lethal(3)Lakers, are haplo-deficient and present in polytene bands. Laker gene product is a muscle component that causes muscle abnormalities.

The basic helix-loop-helix transcription factor Twist is required for normal development of larval and adult somatic muscles in Drosophila. Adult flies normally have six pairs of dorsal longitudinal indirect flight muscles (DLMs), whereas when Twist function is reduced, only three pairs of DLMs are formed. Although twist is expressed in precursors of adult muscles throughout the larval and early pupal stages, we demonstrate that Twist function is required only during the late larval stage for DLM patterning. In wild-type flies, this is just prior to the time when three pairs of persistent larval muscle fibers split longitudinally to form templates for the six pairs of DLMs. By examining sections at various times during pupal development, we found that splitting of the larval muscles does not occur in twist mutants, indicating that Twist function is required to induce major changes in the larval templates prior to differentiation. The function of Twist in larval muscle splitting is likely mediated by myocyte enhancer factor-2 (MEF2) since in Mef2 hypomorphic mutants splitting is also reduced and Mef2 expression is dependent upon Twist. Our findings define specific roles for Twist and MEF2 during pupal myogenesis and demonstrate that these transcription factors function in adult muscle precursor cells to regulate downstream factors controlling muscle cell splitting and morphogenesis. Key Words: Twist; MEF2; Drosophila; adult myogenesis; imaginal discs; patterning.