Size compensation in Drosophila after generalised cell death.

Regeneration is a response mechanism aimed to restore tissues that have been damaged. We are studying in the wing disc of Drosophila the regenerative response to a dose of Ionizing Radiation that kills over 35% of the cells distributed all over the disc. After such treatment the discs are able to restore normal size, indicating there is a mechanism that repairs generalised damage. We have tested the role of the JNK, JAK/STAT and Wg pathways, known to be required for regeneration after localised damage in the disc. We find that after irradiation there is size compensation in the absence of function of these pathways, indicating that they are not necessary for the compensation. Furthermore, we also find that generalised damage does not cause an increase in the proliferation rate of surviving cells. We propose that irradiated discs suffer a developmental delay and resume growth at normal rate until they reach the final stereotyped size. The delay appears to be associated with a developmental reversion, because discs undergo rejuvenation towards an earlier developmental stage. We argue that the response to generalized damage is fundamentally different from that to localized damage, which requires activity of JNK and Wg.

Coordination between cell proliferation and apoptosis after DNA damage in Drosophila.

Exposure to genotoxic stress promotes cell cycle arrest and DNA repair or apoptosis. These "life" or "death" cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, the precise regulation of p53 is essential to maintain tissue homeostasis and to prevent cancer development. However, how cell cycle progression has an impact on p53 cell fate decision-making is mostly unknown. In this work, we demonstrate that Drosophila p53 proapoptotic activity can be impacted by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation-induced apoptosis. We show that p53 binding to the regulatory elements of the proapoptotic genes and its ability to activate their expression is compromised in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 proapoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 proapoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

Role of the Forkhead Transcription Factors Fd4 and Fd5 During Drosophila Leg Development.

Appendage development requires the coordinated function of signaling pathways and transcription factors to pattern the leg along the three main axes: the antero-posterior (AP), proximo-distal (PD), and dorso-ventral (DV). The Drosophila leg DV axis is organized by two morphogens, Decapentaplegic (Dpp), and Wingless (Wg), which direct dorsal and ventral cell fates, respectively. However, how these signals regulate the differential expression of its target genes is mostly unknown. In this work, we found that two members of the Drosophila forkhead family of transcription factors, Fd4 and Fd5 (also known as fd96Ca and fd96Cb), are identically expressed in the ventro-lateral domain of the leg imaginal disc in response to Dpp signaling. Here, we analyze the expression regulation and function of these genes during leg development. We have generated specific mutant alleles for each gene and a double fd4/fd5 mutant chromosome to study their function during development. We highlight the redundant role of the fd4/fd5 genes during the formation of the sex comb, a male specific structure that appears in the ventro-lateral domain of the prothoracic leg.

Specification and Patterning of Drosophila Appendages.

Appendages are external projections of the body that serve the animal for locomotion, feeding, or environment exploration. The appendages of the fruit fly Drosophilamelanogaster are derived from the imaginal discs, epithelial sac-like structures specified in the embryo that grow and pattern during larva development. In the last decades, genetic and developmental studies in the fruit fly have provided extensive knowledge regarding the mechanisms that direct the formation of the appendages. Importantly, many of the signaling pathways and patterning genes identified and characterized in Drosophila have similar functions during vertebrate appendage development. In this review, we will summarize the genetic and molecular mechanisms that lead to the specification of appendage primordia in the embryo and their posterior patterning during imaginal disc development. The identification of the regulatory logic underlying appendage specification in Drosophila suggests that the evolutionary origin of the insect wing is, in part, related to the development of ventral appendages.

Visual hallucinations and HLA class II antigens in cortical dementia.

BACKGROUND: Visual hallucinations are a core feature of dementia with Lewy bodies (DLB) and have been proposed as being part of a narcolepsy-like REM sleep disorder. Selective loss of hypothalamic hypocretin-producing neurons is common to both narcolepsy and the spectrum of Lewy body diseases. We hypothesized that the genetic marker associated with narcolepsy, the HLA class II DR2-DQ6 haplotype, could confer some degree of susceptibility to brainstem-hypothalamic damage leading to the manifestation of visual hallucinations. METHODS: We examined HLA class II haplotypes in 30 patients with prominent visual hallucinations in the context of clinical criteria for DLB and in 30 patients affected by a cortical-type dementia without hallucinations. RESULTS: No significant differences were found in the distribution of DR and DQ antigens. CONCLUSIONS: We conclude that hypothalamic vulnerability in different diseases is not mediated by a common HLA haplotype.