RESUMO
BACKGROUND: Radial forearm free flap phalloplasty (RFFF) is a set of complex reconstructive procedures aimed at creating an aesthetic and functional penis in transgender patients. Sensory recovery in the neophallus and donor site is crucial for optimizing outcomes, but the few prior studies that exist assess neophallus sensation at limited locations and time points. The purpose of this study was to prospectively quantify sensory outcomes in the neophallus and donor site following RFFF phalloplasty. METHODS: Sensation testing occurred prospectively over February 2019-January 2021 on Stage 1 RFFF phalloplasty patients using the Pressure Specified Sensory Device (PSSD). On the neophallus, one-point discrimination (1PS) pressure threshold and lengthwise sensory recovery were measured at six circumferential locations proximally to distally. On the donor site, 1PS was measured at three locations on the donor hand. RESULTS: Nineteen patients were included (average age 34.0 years old, range 18-53 years). Among patients that received neophallus testing (n = 13), eight had at least two follow-up appointments. Six of these patients had sensation as of their most recent measurement (75.0%), with an average of 73 days to regain sensation. There was a significantly greater proportion of patients with sensation at the right ventral (80.0% after 3 months vs. 11.1%-60.0% before 3 months, p = 0.024) and right lateral (100.0% after 3 months vs. 11.1%-60.0% before 3 months, p = 0.004) aspects of the neophallus over time. Pressure required to elicit sensation decreased by 18.0% from 1 week-1 month postoperatively to 3-7.7 months postoperatively in the right ventral neophallus (96.2 g/mm2 ± 11.3 g/mm2 to 56.6 ± 39.9 g/mm2, p = 0.037). Among patients that received donor site testing (n = 11), mixed effects regression analysis with random intercepts demonstrated significant changes in the thumb (3.4 g/mm2 ± 1.4 g/mm2, p < 0.05) and webspace (13.5 g/mm2 ± 4.9 g/mm2, p < 0.01) that returned to baseline at 3 months postoperatively (1.7 g/mm2 ± 1.0 g/mm2, p > 0.05, and 2.3 g/mm2 ± 4.0 g/mm2, p > 0.05, respectively). CONCLUSION: This pilot study demonstrates that quantitative sensory testing can be used to monitor post-phalloplasty sensory changes. Recovery was significantly associated with contralateral (i.e, right side in a left forearm RFF) aspects of the neophallus, suggesting a possible pattern of circumferential sensory innervation via RFFF sensory nerves. Future studies with a larger sample size and longer follow-ups are necessary to fully characterize sensory recovery in phalloplasty patients.
Assuntos
Antebraço , Retalhos de Tecido Biológico , Pênis , Sítio Doador de Transplante , Humanos , Masculino , Projetos Piloto , Retalhos de Tecido Biológico/transplante , Estudos Prospectivos , Adulto , Pessoa de Meia-Idade , Antebraço/cirurgia , Pênis/cirurgia , Pênis/inervação , Sítio Doador de Transplante/cirurgia , Adulto Jovem , Adolescente , Procedimentos de Cirurgia Plástica/métodos , Feminino , Cirurgia de Readequação Sexual/métodos , Sensação/fisiologia , Resultado do Tratamento , Recuperação de Função Fisiológica , Transplante Peniano , FaloplastiaRESUMO
Extracellular vesicles (EVs) are released by many cell types, including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating endosomal sorting complex required for transport (ESCRT) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo evenness interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell-autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Complexos Endossomais de Distribuição Requeridos para Transporte , Vesículas Extracelulares , Neurônios Motores , Transdução de Sinais , Sinapses , Animais , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Vesículas Extracelulares/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Sinapses/metabolismo , Neurônios Motores/metabolismo , Autofagia , Sinaptotagminas/metabolismo , Sinaptotagminas/genética , Neuroglia/metabolismoRESUMO
Extracellular vesicles (EVs) are released by many cell types including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo Evenness Interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.
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At synapses, chemical neurotransmission mediates the exchange of information between neurons, leading to complex movement, behaviors, and stimulus processing. The immense number and variety of neurons within the nervous system make discerning individual neuron populations difficult, necessitating the development of advanced neuronal labeling techniques. In Drosophila, Bruchpilot-Short and mCD8-GFP, which label presynaptic active zones and neuronal membranes, respectively, have been widely used to study synapse development and organization. This labeling is often achieved via the expression of 2 independent constructs by a single binary expression system, but expression can weaken when multiple transgenes are expressed by a single driver. Recent work has sought to circumvent these drawbacks by developing methods that encode multiple proteins from a single transcript. Self-cleaving peptides, specifically 2A peptides, have emerged as effective sequences for accomplishing this task. We leveraged 2A ribosomal skipping peptides to engineer a construct that produces both Bruchpilot-Short-mStraw and mCD8-GFP from the same mRNA, which we named SynLight. Using SynLight, we visualized the putative synaptic active zones and membranes of multiple classes of olfactory, visual, and motor neurons and observed the correct separation of signal, confirming that both proteins are being generated separately. Furthermore, we demonstrate proof of principle by quantifying synaptic puncta number and neurite volume in olfactory neurons and finding no difference between the synapse densities of neurons expressing SynLight or neurons expressing both transgenes separately. At the neuromuscular junction, we determined that the synaptic puncta number labeled by SynLight was comparable to the endogenous puncta labeled by antibody staining. Overall, SynLight is a versatile tool for examining synapse density in any nervous system region of interest and allows new questions to be answered about synaptic development and organization.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Sinapses/genética , Junção Neuromuscular/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Neurônios Motores/metabolismo , PeptídeosRESUMO
At synapses, chemical neurotransmission mediates the exchange of information between neurons, leading to complex movement behaviors and stimulus processing. The immense number and variety of neurons within the nervous system makes discerning individual neuron populations difficult, necessitating the development of advanced neuronal labeling techniques. In Drosophila , Bruchpilot-Short and mCD8-GFP, which label presynaptic active zones and neuronal membranes, respectively, have been widely used to study synapse development and organization. This labeling is often achieved via expression of two independent constructs by a single binary expression system, but expression can weaken when multiple transgenes are expressed by a single driver. Ensuring adequate expression of each transgene is essential to enable more complex experiments; as such, work has sought to circumvent these drawbacks by developing methods that encode multiple proteins from a single transcript. Self-cleaving peptides, specifically 2A peptides, have emerged as effective sequences for accomplishing this task. We leveraged 2A ribosomal skipping peptides to engineer a construct that produces both Bruchpilot-Short and mCD8-GFP from the same mRNA, which we named SynLight. Using SynLight, we visualized the putative synaptic active zones and membranes of multiple classes of olfactory, visual, and motor neurons and observed correct separation of signal, confirming that both proteins are being generated separately. Furthermore, we demonstrate proof-of-principle by quantifying synaptic puncta number and neurite volume in olfactory neurons and finding no difference between the synapse densities of neurons expressing SynLight or neurons expressing both transgenes separately. At the neuromuscular junction, we determined that synaptic puncta number labeled by SynLight was comparable to endogenous puncta labeled by antibody staining. Overall, SynLight is a versatile tool for examining synapse density in any nervous system region of interest and allows new questions to be answered about synaptic development and organization.
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Chemical neurotransmission occurs at specialized contacts where neurotransmitter release machinery apposes neurotransmitter receptors to underlie circuit function. A series of complex events underlies pre- and postsynaptic protein recruitment to neuronal connections. To better study synaptic development in individual neurons, we need cell-type-specific strategies to visualize endogenous synaptic proteins. Although presynaptic strategies exist, postsynaptic proteins remain less studied because of a paucity of cell-type-specific reagents. To study excitatory postsynapses with cell-type specificity, we engineered dlg1[4K], a conditionally labeled marker of Drosophila excitatory postsynaptic densities. With binary expression systems, dlg1[4K] labels central and peripheral postsynapses in larvae and adults. Using dlg1[4K], we find that distinct rules govern postsynaptic organization in adult neurons, multiple binary expression systems can concurrently label pre- and postsynapse in a cell-type-specific manner, and neuronal DLG1 can sometimes localize presynaptically. These results validate our strategy for conditional postsynaptic labeling and demonstrate principles of synaptic organization.
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Drosophila , Sinapses , Animais , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Neurônios/fisiologia , Receptores de Neurotransmissores/metabolismoRESUMO
Developing synapses mature through the recruitment of specific proteins that stabilize presynaptic and postsynaptic structure and function. Wnt ligands signaling via Frizzled (Fz) receptors play many crucial roles in neuronal and synaptic development, but whether and how Wnt and Fz influence synaptic maturation is incompletely understood. Here, we show that Fz2 receptor cleavage via the γ-secretase complex is required for postsynaptic development and maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to recruit postsynaptic scaffolding and cytoskeletal proteins, leading to behavioral deficits. Introducing presenilin mutations linked to familial early-onset Alzheimer's disease into flies leads to synaptic maturation phenotypes that are identical to those seen in null alleles. This conserved role for γ-secretase in synaptic maturation and postsynaptic development highlights the importance of Fz2 cleavage and suggests that receptor processing by proteins linked to neurodegeneration may be a shared mechanism with aspects of synaptic development.
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Proteínas de Drosophila , Drosophila , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Receptores Frizzled/metabolismo , Receptores Wnt/metabolismo , Sinapses/metabolismoRESUMO
An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)30+) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+). Through an unbiased large-scale screen of (G4C2)49-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+-derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.
Assuntos
Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Regulação da Expressão Gênica/genética , Proteínas Nucleares/genética , Animais , Drosophila melanogaster , Humanos , Camundongos , Fatores de Transcrição/genéticaRESUMO
Nibbler (Nbr) is a 3'-to-5' exonuclease that trims the 3'end of microRNAs (miRNAs) to generate different length patterns of miRNAs in Drosophila. Despite its effect on miRNAs, we lack knowledge of its biological significance and whether Nbr affects other classes of small RNAs such as piRNAs and endo-siRNAs. Here, we characterized the in vivo function of nbr by defining the Nbr protein expression pattern and loss-of-function effects. Nbr protein is enriched in the ovary and head. Analysis of nbr null animals reveals adult-stage defects that progress with age, including held-up wings, decreased locomotion, and brain vacuoles, indicative of accelerated age-associated processes upon nbr loss. Importantly, these effects depend on catalytic residues in the Nbr exonuclease domain, indicating that the catalytic activity is responsible for these effects. Given the impact of nbr on miRNAs, we also analyzed the effect of nbr on piRNA and endo-siRNA lengths by deep-sequence analysis of libraries from ovaries. As with miRNAs, nbr mutation led to longer length piRNAs - an effect that was dependent on the catalytic residues of the exonuclease domain. These analyses indicate a role of nbr on age-associated processes and to modulate length of multiple classes of small RNAs including miRNAs and piRNAs in Drosophila.
Assuntos
Envelhecimento , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Exorribonucleases/metabolismo , RNA Interferente Pequeno/genética , Animais , Proteínas Argonautas/metabolismo , Drosophila melanogaster/genética , Feminino , MicroRNAs/genética , Ovário/metabolismoRESUMO
Neural regeneration is a fascinating process with profound impact on human health, such that defining biological and genetic pathways is of interest. Here we describe an in vivo preparation for neuronal regeneration in the adult Drosophila. The nerve along the anterior margin of the wing is comprised of ~225 neurons that send projections into the central neuropil (thorax). Precise ablation can be induced with a pulsed laser to sever the entire axonal tract. The animal can be recovered, and response to injury assessed over time. Upon ablation, there is local loss of axons near the injury site, scar formation, a rapid impact on the cytoskeleton, and stimulation of hemocytes. By 7d, ~50% of animals show nerve regrowth, with axons from the nerve cells extending down towards the injury or re-routing. Inhibition of JNK signaling promotes regrowth through the injury site, enabling regeneration of the axonal tract.
Assuntos
Axônios/fisiologia , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/fisiopatologia , Animais , Movimento Celular , Citoesqueleto/metabolismo , Drosophila , Hemócitos/fisiologia , Hemolinfa/fisiologia , Sistema de Sinalização das MAP Quinases , Masculino , Neuroglia/fisiologia , Asas de Animais/inervaçãoRESUMO
BACKGROUND: D. melanogaster is increasingly used as a lipid metabolism model, but the D. melanogaster metabolome is not well studied. A number of studies strongly suggest that lipid metabolism is linked to sexual behavior and gametogenesis. FINDINGS: We determined the levels of 400 different lipids in the non-gonadal soma of D. melanogaster females and males. We found higher levels of saturated cholesterol esters and lysophosphatidylcholine in males, and higher levels of polyunsaturated cholesterol esters in females. We also determined the levels of these lipids in females and males without a germline to determine if the absence of gamete "sinks" for metabolic products, such as yolk and lipid deposits in eggs, altered somatic lipid profiles. We observed little change in lipid profiles between these samples. CONCLUSIONS: Overall lipid compositions are similar between the sexes, although there are differences in saturation states of two lipid classes, where saturated fatty acids were male-biased and polyunsaturated fatty acids were female-biased. The presence of a germline did not significantly influence lipid profiles, raising the possibility that germline-dependent changes in metabolic gene expression patterns serve a homeostatic purpose.
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BACKGROUND: Drosophila females commit tremendous resources to egg production and males produce some of the longest sperm in the animal kingdom. We know little about the coordinated regulation of gene expression patterns in distant somatic tissues that support the developmental cost of gamete production. RESULTS: We determined the non-gonadal gene expression patterns of Drosophila females and males with or without a germline. Our results show that germline-dependent expression in the non-gonadal soma is extensive. Interestingly, gene expression patterns and hormone titers are consistent with a hormone axis between the gonads and non-gonadal soma. CONCLUSIONS: The germline has a long-range influence on gene expression in the Drosophila sexes. We suggest that this is the result of a germline/soma hormonal axis.
Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Perfilação da Expressão Gênica , Células Germinativas/metabolismo , Análise de Variância , Animais , Drosophila melanogaster/metabolismo , Retroalimentação Fisiológica , Feminino , Genótipo , Gônadas , Hormônios/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Caracteres Sexuais , Comportamento Sexual AnimalRESUMO
Both genome content and deployment contribute to phenotypic differences between species. Sex is the most important difference between individuals in a species and has long been posited to be rapidly evolving. Indeed, in the Drosophila genus, traits such as sperm length, genitalia, and gonad size are the most obvious differences between species. Comparative analysis of sex-biased expression should deepen our understanding of the relationship between genome content and deployment during evolution. Using existing and newly assembled genomes, we designed species-specific microarrays to examine sex-biased expression of orthologues and species-restricted genes in D. melanogaster, D. simulans, D. yakuba, D. ananassae, D. pseudoobscura, D. virilis and D. mojavensis. We show that averaged sex-biased expression changes accumulate monotonically over time within the genus. However, different genes contribute to expression variance within species groups compared to between groups. We observed greater turnover of species-restricted genes with male-biased expression, indicating that gene formation and extinction may play a significant part in species differences. Genes with male-biased expression also show the greatest expression and DNA sequence divergence. This higher divergence and turnover of genes with male-biased expression may be due to high transcription rates in the male germline, greater functional pleiotropy of genes expressed in females, and/or sexual competition.
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Drosophila/genética , Evolução Molecular , Regulação da Expressão Gênica/genética , Caracteres Sexuais , Animais , Drosophila/classificação , Feminino , Genoma de Inseto/genética , Masculino , Especificidade da EspécieRESUMO
X chromosomes evolve differently from autosomes, but general governing principles have not emerged. For example, genes with male-biased expression are under-represented on the X chromosome of D. melanogaster, but are randomly distributed in the genome of Anopheles gambiae. In direct global profiling experiments using species-specific microarrays, we find a nearly identical paucity of genes with male-biased expression on D. melanogaster, D. simulans, D. yakuba, D. ananassae, D. virilis and D. mojavensis X chromosomes. We observe the same under-representation on the neo-X of D. pseudoobscura. It has been suggested that precocious meiotic silencing of the X chromosome accounts for reduced X chromosome male-biased expression in nematodes, mammals and Drosophila. We show that X chromosome genes with male-biased expression are under-represented in somatic cells and in mitotic male germ cells. These data are incompatible with simple X chromosome inactivation models. Using expression profiling and comparative sequence analysis, we show that selective gene extinction on the X chromosome, creation of new genes on autosomes and changed genomic location of existing genes contribute to the unusual X chromosome gene content.
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Drosophila/genética , Regulação da Expressão Gênica/genética , Caracteres Sexuais , Cromossomo X/genética , Animais , Drosophila/classificação , Feminino , Perfilação da Expressão Gênica , Masculino , Modelos Genéticos , Inativação do Cromossomo XRESUMO
Menin is a tumor suppressor required to prevent multiple endocrine neoplasia in humans. Mammalian menin protein is associated with chromatin modifying complexes and has been shown to bind a number of nuclear proteins, including the transcription factor JunD. Menin shows bidirectional effects acting positively on c-Jun and negatively on JunD. We have produced protein null alleles of Drosophila menin (mnn1) and have over expressed the Mnn1 protein. Flies homozygous for protein-null mnn1 alleles are viable and fertile. Localized over-expression of Mnn1 causes defects in thoracic closure, a phenotype that sometimes results from insufficient Jun activity. We observed complex genetic interactions between mnn1 and jun in different developmental settings. Our data support the idea that one function of menin is to modulate Jun activity in a manner dependent on the cellular context.
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Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/genética , Alelos , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/genética , Olho/anatomia & histologia , Olho/embriologia , Dados de Sequência Molecular , Fenótipo , Proteínas Proto-Oncogênicas c-fos/fisiologia , Proteínas Proto-Oncogênicas c-jun/fisiologia , Homologia de Sequência de Aminoácidos , Tórax/metabolismoRESUMO
BACKGROUND: Drosophila melanogaster females have two X chromosomes and two autosome sets (XX;AA), while males have a single X chromosome and two autosome sets (X;AA). Drosophila male somatic cells compensate for a single copy of the X chromosome by deploying male-specific-lethal (MSL) complexes that increase transcription from the X chromosome. Male germ cells lack MSL complexes, indicating that either germline X-chromosome dosage compensation is MSL-independent, or that germ cells do not carry out dosage compensation. RESULTS: To investigate whether dosage compensation occurs in germ cells, we directly assayed X-chromosome transcripts using DNA microarrays and show equivalent expression in XX;AA and X;AA germline tissues. In X;AA germ cells, expression from the single X chromosome is about twice that of a single autosome. This mechanism ensures balanced X-chromosome expression between the sexes and, more importantly, it ensures balanced expression between the single X chromosome and the autosome set. Oddly, the inactivation of an X chromosome in mammalian females reduces the effective X-chromosome dose and means that females face the same X-chromosome transcript deficiency as males. Contrary to most current dosage-compensation models, we also show increased X-chromosome expression in X;AA and XX;AA somatic cells of Caenorhabditis elegans and mice. CONCLUSION: Drosophila germ cells compensate for X-chromosome dose. This occurs by equilibrating X-chromosome and autosome expression in X;AA cells. Increased expression of the X chromosome in X;AA individuals appears to be phylogenetically conserved.
Assuntos
Mecanismo Genético de Compensação de Dose , Drosophila melanogaster/genética , Cromossomo X , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Ovário/metabolismo , Testículo/metabolismo , Transcrição GênicaRESUMO
BACKGROUND: Sexual dimorphism results in the formation of two types of individuals with specialized reproductive roles and is most evident in the germ cells and gonads. RESULTS: We have undertaken a global analysis of transcription between the sexes using a 31,464 element FlyGEM microarray to determine what fraction of the genome shows sex-biased expression, what tissues express these genes, the predicted functions of these genes, and where these genes map onto the genome. Females and males (both with and without gonads), dissected testis and ovary, females and males with genetically ablated germlines, and sex-transformed flies were sampled. CONCLUSIONS: Using any of a number of criteria, we find extensive sex-biased expression in adults. The majority of cases of sex differential gene expression are attributable to the germ cells. There is also a large class of genes with soma-biased expression. There is little germline-biased expression indicating that nearly all genes with germline expression also show sex-bias. Monte Carlo simulations show that some genes with sex-biased expression are non-randomly distributed in the genome.
Assuntos
Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Ovário/química , Ovário/metabolismo , Testículo/química , Testículo/metabolismo , Animais , Northern Blotting/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Genes de Insetos/genética , Genes de Insetos/fisiologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Mensageiro/genética , Projetos de Pesquisa , Fatores SexuaisRESUMO
Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1-like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear. It may partner with junD, NF-kB, PEM, SMAD3, RPA2, FANCD2, NM23beta, nonmuscle myosin heavy chain II-A, GFAP, and/or vimentin. These partners have not clarified menin's pathways in normal or tumor tissues. Animal models have opened approaches to menin pathways. Local overexpression of menin in Drosophila reveals its interaction with the jun-kinase pathway. The Men1+/- mouse has robust MEN1; its most important difference from human MEN1 is marked hyperplasia of pancreatic islets, a tumor precursor stage.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla/fisiopatologia , Proteínas Proto-Oncogênicas/genética , Animais , Humanos , Neoplasia Endócrina Múltipla/patologiaRESUMO
Females and males often exhibit conspicuous morphological, physiological and behavioral differences. Similarly, gene expression profiles indicate that a large portion of the genome is sex-differentially deployed, particularly in the germ line. Because males and females are so fundamentally different, each sex is likely to have a different optimal gene expression profile that is never fully achieved in either sex because of antagonistic selection in females versus males. Males are hemizygous for the X chromosome, which means that recessive male-favorable de novo mutations on the X chromosome are subject to immediate selection. In females, a recessive female-favorable mutation on one of two X chromosomes is not available for selection until it becomes frequent enough in the local population to result in homozygous individuals. Given that most mutations are recessive, one would expect that genes or alleles favoring males should accumulate on the X chromosome. Recent microarray work in Drosophila and C. elegans clearly shows the opposite. Why is the X chromosome a highly disfavored location for genes with male-biased expression in these animals?