RESUMEN
Human neurodegenerative disorders are typified by late onset cell loss in specific brain regions and stereotypic neuroanatomical and behavioral aberrations. Recent studies suggest that molecular genetic approaches in Drosophila may shed important new light on conserved mechanisms underlying such disorders.
Asunto(s)
Drosophila/genética , Genes de Insecto , Degeneración Nerviosa/genética , Animales , Ácido Glutámico , Humanos , Repeticiones de Microsatélite , MutaciónRESUMEN
Expansion of triplet repeats has been seen to underlie several disorders that manifest anticipation. Clinical evidence suggests that anticipation occurs in the major psychoses. We studied the distribution of repeat sizes at the Machado-Joseph disease (MJD) locus in a group of patients with the major psychoses. We did not find any large expansions, though 2 patients had alleles that were two repeats larger than in our controls. The difference in allele sizes was larger in the patient sample as compared to the controls. The effect of such large differences might be of functional significance.
Asunto(s)
Genoma Humano , Trastornos Psicóticos/genética , Secuencias Repetitivas de Aminoácido , Adulto , Femenino , Marcadores Genéticos , Humanos , MasculinoRESUMEN
The molecular genetic analyses (PCR and Southern hybridization) of Indian patients with myotonic dystrophy (DM) were carried out to determine the degree of repeat expansion and an attempt was made to correlate the repeat number with disease severity. A scoring system based on the salient clinical features was devised to objectively assess the disease severity. The repeat expansion was seen in 11 of 12 patients examined and showed an inverse correlation with the age of onset confirming the phenomenon of anticipation. This was further established in the two pedigrees studied, clearly demonstrating both clinical and genetic anticipation. The clinical severity score, however, did not correlate well with the repeat number. Nonetheless, such molecular genetic analyses may have immense value as a screening procedure to identify premutations as well as in prenatal diagnoses.
Asunto(s)
Distrofia Miotónica/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas , Secuencias Repetitivas de Ácidos Nucleicos , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Quinasa de Distrofia Miotónica , LinajeRESUMEN
A chromosomal element (C) of an interspecific hybrid of D. miranda (females) and D. persimilis (males) represented a unique situation, where between its two homologous, one derived from an X chromosome (X2 of miranda) and the other from an autosome (3rd chromosome of persimilis). In cytological preparations of polytene nuclei, the X chromosomal homolog in hybrid males exhibited the male-X like inflated structure, known as prerequisite for hypertranscription; whereas the autosomal homolog existed as an haploid autosomal arm. In hybrid females, both the homologs had similar diameter and stainability. This difference in cytomorphology of the X2 homolog between two sexes made the C element potential to transcribe higher in males than in females, raising the inevitable question of compensation. Cellular autoradiography, using 3H-UR, was employed to measure the total transcription of the C element (X2 + 3rd) in hybrid sexes. Results revealed that, although the X2-homolog was hyperactive in males, the total transcription of the C element was equal (relative to autosomal transcription) in both hybrid sexes, and this was achieved in expense of the transcription of the 3rd chromosomal homolog in males. Thus, apart from X-chromosomal and autosomal dosage compensation, the existence of an X-autosomal dosage compensation in Drosophila is evident in the present work.
Asunto(s)
Compensación de Dosificación (Genética) , Drosophila/genética , Cromosoma X , Animales , Cromosomas , Cruzamientos Genéticos , Femenino , Hibridación Genética , MasculinoAsunto(s)
Replicación del ADN , Drosophila/genética , Cromosoma Y/ultraestructura , Animales , Autorradiografía , MasculinoAsunto(s)
Replicación del ADN , Drosophila melanogaster/genética , Transcripción Genética , Cromosoma X , Animales , FemeninoRESUMEN
Developmental expression of the heat shock inducible non-protein coding hsr-omega gene in several larval and adult tissues of Drosophila melanogaster was examined by in situ hybridization to transcripts in intact organs and by X-gal staining in the germline transformants and carrying the lacZ reporter gene under the control of hsr-omega promoter. This gene is expressed in a specific spatial pattern in all the larval and adult tissue types examined; however, its transcripts were specifically absent in certain gonadal cell types like the male as well as female gonial cells and in follicle cells and oocytes in ovary. All polytenised tissues like the prothoracic and salivary glands, certain regions of larval gut and the Malpighian tubules showed a greater abundance of hsr-omega transcripts with a strong hybridization in nuclei. Our results with promoter deletion variant germline transformants suggest that a region between -346bp to -844bp upstream contains major regulatory elements for developmental expression of this gene in most of the larval and adult tissues examined; however, this region is not sufficient for its normal expression in male and female reproductive systems. An analysis of the base sequence of the hsr-omega promoter (upto - 844 bp) reveals putative ecdysone receptor element half-sites and two GAGA factor binding sites which may be involved in its developmental expression and its ready inducibility. The widespread expression in most tissue types and the known lethality associated with its homozygous deletion, suggest that the variety of non-protein coding transcripts of the hsr-omega gene have vital "house-keeping" functions.
Asunto(s)
Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Genes de Insecto , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , ADN , Drosophila melanogaster/crecimiento & desarrollo , Genes Reporteros , Respuesta al Choque Térmico , Operón Lac , Datos de Secuencia Molecular , ARN/metabolismoRESUMEN
In Drosophila, the fish-hook (fish) gene encodes a Sox protein essential for embryonic segmentation and nervous system organization. In this study we examined potential functional roles of fish in postembryonic developmental processes, including those involved in adult appendage development. We show here that Fish protein is expressed in discrete patterns in the larval eye-antennal and leg imaginal discs, the central nervous system, the hindgut, and salivary glands. Genetic mosaic studies indicated that fish function is required for the growth or survival of imaginal cells, and the expression of engrailed and wingless. Ectopic expression of Fish protein resulted in severe disruption of adult structures; legs and antennae were truncated and eye formation was suppressed. These morphological defects were correlated with altered expression patterns of the wingless, decapentaplegic, and bric-a-brac genes. Finally, analysis of truncated versions of Fish protein indicated that the HMG domain was sufficient for Fish nuclear localization and that removal of the transcriptional activation domain did not eliminate Fish function. While Sox proteins have been shown to be important for eye and limb formation in vertebrates, these data provide the first evidence for Sox protein functions in appendage development in invertebrates.
Asunto(s)
Proteínas de Unión al ADN , Proteínas de Drosophila , Drosophila/crecimiento & desarrollo , Drosophila/genética , Desarrollo Embrionario , Proteínas del Grupo de Alta Movilidad/genética , Factores de Transcripción , Animales , Secuencia de Bases , Cartilla de ADN , Ojo/embriología , Microscopía Electrónica de Rastreo , Factores de Transcripción SOXRESUMEN
During Drosophila embryogenesis the CNS midline cells have organizing activities that are required for proper elaboration of the axon scaffold and differentiation of neighboring neuroectodermal and mesodermal cells. CNS midline development is dependent on Single-minded (Sim), a basic-helix-loop-helix (bHLH)-PAS transcription factor. We show here that Fish-hook (Fish), a Sox HMG domain protein, and Drifter (Dfr), a POU domain protein, act in concert with Single-minded to control midline gene expression. single-minded, fish-hook, and drifter are all expressed in developing midline cells, and both loss- and gain-of-function assays revealed genetic interactions between these genes. The corresponding proteins bind to DNA sites present in a 1 kb midline enhancer from the slit gene and regulate the activity of this enhancer in cultured Drosophila Schneider line 2 cells. Fish-hook directly associates with the PAS domain of Single-minded and the POU domain of Drifter; the three proteins can together form a ternary complex in yeast. In addition, Fish can form homodimers and also associates with other bHLH-PAS and POU proteins. These results indicate that midline gene regulation involves the coordinate functions of three distinct types of transcription factors. Functional interactions between members of these protein families may be important for numerous developmental and physiological processes.