RESUMO
Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted. Inpp5e limits the ciliary levels of inhibitors of Hh signaling, including Gpr161 and the PI(4,5)P2-binding protein Tulp3. Increasing ciliary PI(4,5)P2 levels or conferring the ability to bind PI(4)P on Tulp3 increases the ciliary localization of Tulp3. Lowering Tulp3 in cells lacking Inpp5e reduces ciliary Gpr161 levels and restores Hh signaling. Therefore, Inpp5e regulates ciliary membrane phosphoinositide composition, and Tulp3 reads out ciliary phosphoinositides to control ciliary protein localization, enabling Hh signaling.
Assuntos
Cílios/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas Hedgehog/metabolismo , Fosfatidilinositóis/metabolismo , Transdução de Sinais , Animais , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Modelos Biológicos , Células NIH 3T3 , Fosfatidilinositol 4,5-Difosfato , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolases , Transporte Proteico , Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The morphological diversity of animals, fungi, plants, and other multicellular organisms stems from the fact that each lineage acquired multicellularity independently. A prerequisite for each origin of multicellularity was the evolution of mechanisms for stable cell-cell adhesion or attachment. Recent advances in comparative genomics and phylogenetics provide critical insights into the evolutionary foundations of cell adhesion. Reconstructing the evolution of cell junction proteins in animals and their unicellular relatives exemplifies the roles of co-option and innovation. Comparative studies of volvocine algae reveal specific molecular changes that accompanied the evolution of multicellularity in Volvox. Comparisons between animals and Dictyostelium show how commonalities and differences in the biology of unicellular ancestors influenced the evolution of adhesive mechanisms. Understanding the unicellular ancestry of cell adhesion helps illuminate the basic cell biology of multicellular development in modern organisms.
Assuntos
Evolução Biológica , Adesão Celular , Animais , Eucariotos/citologia , Matriz Extracelular , Fungos/citologia , Células VegetaisRESUMO
Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans.
Assuntos
Células Eucarióticas/metabolismo , Genoma/genética , Filogenia , Animais , Adesão Celular , Sequência Conservada , Células Eucarióticas/classificação , Células Eucarióticas/citologia , Evolução Molecular , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Especiação Genética , Proteínas Hedgehog/química , Proteínas Hedgehog/genética , Humanos , Íntrons/genética , Fosfotirosina/metabolismo , Estrutura Terciária de Proteína/genética , Receptores Notch/química , Receptores Notch/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Cadherin-mediated cell adhesion and signaling is essential for metazoan development and yet is absent from all other multicellular organisms. We found cadherin genes at numbers similar to those observed in complex metazoans in one of the closest single-celled relatives of metazoans, the choanoflagellate Monosiga brevicollis. Because the evolution of metazoans from a single-celled ancestor required novel cell adhesion and signaling mechanisms, the discovery of diverse cadherins in choanoflagellates suggests that cadherins may have contributed to metazoan origins.
Assuntos
Evolução Biológica , Caderinas/química , Caderinas/genética , Eucariotos/química , Células Eucarióticas/química , Citoesqueleto de Actina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Caderinas/fisiologia , Adesão Celular , Ciona intestinalis/química , Cnidários/química , Drosophila melanogaster/química , Células Eucarióticas/fisiologia , Camundongos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Sequências Repetitivas de Aminoácidos , Transdução de Sinais , Tirosina/metabolismo , Domínios de Homologia de srcRESUMO
The ATP-binding cassette transporter A1 (ABCA1) gene, a major regulator of high-density lipoprotein (HDL) metabolism, utilizes several transcriptional start sites. The pattern of transcripts among tissues and cells differed significantly. The longest (class 1) transcripts were abundant in adult brain and fetal tissues. Class 2 transcripts predominated in most other tissues. The shortest (class 3) transcripts were present mainly in adult liver and lung. To study the biochemical significance of changes in transcript distribution, two cell models were compared. In primary human fibroblasts, upregulation of mRNA levels by oxysterols and retinoic acid increased the relative proportion of class 2 transcript compared to class 1. Phorbol ester stimulated human macrophage-derived THP-1 cells increased the abundance of class 1 transcripts relative to class 2. In both cell lines class 3 transcript levels were minimal and unchanged. It is shown here for the first time that the regulation of ABCA1 mRNA levels exploits the use of alternative transcription start sites.
