cilios - bc

CILIOS

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9+0


Anclaje a la membrana plasmtica

Regula la entrada y salida de cargo al cilio

Anclaje del cilio. Puede llegar hasta Golgi, funcionando en el trfico de Golgi cilio.

Protena particular: rootletin

Area de anclaje de los microtbulos del cilio

CUERPO BASAL


Las clulas RPE1fueron crecidas encoverslips hastaconfluencia ycortadas segn elesquema.

Molla-Herman et al. (2010). J Cell Sci 123: 1785-1794.

EL BOLSILLO CILIAR


Current Opinion in Cell Biology 2010, 22:541546


Microvilli Extension of plasma membrane

Abundant in intestine and kidneys where they increase the cell surface area and thus increase absorption)

Highly modified in some special sense organs like the ears

Normally many on each cell One tenth to one twentieth

size of cilia


CLASIFICACIN DE LOS CILIOS

En humanos, se pueden reconocer cuatro tipos de cilios:

a) Cilios mviles de estructura 9 + 2

b) Cilios mviles de estructura 9 + 0 (cilios nodales)

c) Cilios no mviles de estructura 9 + 2 (kinocilia de clulas del pelo en odo)

d) Cilios no mviles de estructura 9 + 0 (cilio primario)


Flagella

Similar to cilia but longer Usually only one per cell Move the cell itself in wave-like fashion Example: sperm cell


Cilia and flagella share a common ultrastructure: A core of microtubules sheathed by the plasma

membrane A basal body that anchors the cilium or flagellum A motor protein called dynein, which drives the

bending movements of a cilium or flagellum


LE 6-25a

Dynein walking

Microtubuledoublets ATP

Dynein arm


LE 6-25b

Wavelike motion

Cross-linkingproteins insideouter doublets

ATP

Anchoragein cell

Effect of cross-linking proteins


MOVIMIENTO CILIAR

A) PENDULAR. El cilio est rgido y se flexiona en su base

B) UNCIFORME (el ms comn en metazoos). El cilio se dobla y adquiere forma de gancho

C) INFUNDIBULIFORME. Rota describiendo una figura cnica

D) ONDULANTE. Caracterstico de flagelos


KINOCILIA


CILIOS NODALES

Sndrome de Kartagener:


CILIOS NODALES


CILIAS NODALES


EL CILIO PRIMARIO


El cilio primario es una organela generalizada en clulas de vertebrados. Slo no ha sido identificado en clulas de origen mieloide y linfoide.

Estructura del Axonema de 9 + 0. Al parecer, ausencia de Dinenaen el cilio primario, de all que no sera una estructura mvil.

Rodeado de una membrana, continua con la membrana plasmtica, si bien hay estudios que parecen demostrar la presencia de protenas especficas en la membrana a nivel del cilio.

En muchas clulas, el clio primario se ubica en una invaginacin de la clula, pero no es general, y en muchas clulas el cilio se proyecta hacia afuera.

Al igual que todos los cilios, se forma a partir de un cuerpo basal originado de un centrolo.


Hasta hace poco, se dudaba sobre la funcin del cilio primario.Se manejaron tres hiptesis:1.- Sera una organela vestigial heredada de un ancestro cuyas clulas tenan cilios mviles.

2.- El cilio primario estara involucrado en el control del ciclo celular.

3.- El cilio primario es una organela sensora.Esta hiptesis es sugerida por el hecho que las cilias son usadas como organelas sensoras en eucariotes inferiores y que estructuras sensoriales como el sistema visual y ofatorio de vertebrados utilizan cilias modificadas.


Cilio primario en rin:

Enfermedad del rin poliqustico (PKD)

Mutaciones en gen Tg737 en ratones


Primary cilia in the kidney of Tg737 mutant mice are shorter than normal.

Pazour G J et al. J Cell Biol 2000;151:709-718

2000 The Rockefeller University Press


Sequence and structure of the Chlamydomonas IFT88 protein.




Sequence and structure of the Chlamydomonas IFT88 protein.



La protena IFT88 de Chlamydomonas es homloga a Tg737 de ratn y de humanos.


Ultrastructure of the ift88-1 flagella.



Ultrastructure of the ift88-1 flagella. The flagella on ift88-1 mutant cells are very short and the microtubules do not extend beyond the transition zone (arrows). The microtubules in wild-type cells start at the basal body, extend through the transition zone, and continue on to the flagellar tip. The wild-type flagellum shown here leaves the plane of section shortly after passing through the cell wall.


RIN POLiQUSTICO

PROLIFERACIN ANORMAL

En humanos: dos mutaciones llevan a PKD: polycystin-1 (protena de membrana) y polycystin-2 (un canal de calcio)

El cilio primario analiza el estado del epitelio renal como una paso previo a desencadenar un proceso de proliferacin/diferenciacin/apoptosis.


RIN POLIQUSTICOOTRA HIPTESIS:


Fig. 2. Primary cilia of kidney epithelial cells sense urine flow and control cell proliferation.

V Singla, J F Reiter Science 2006;313:629-633Published by AAAS

Primary cilia of kidney epithelial cells sense urine flow and control cell proliferation. (A) Deflection of the primary cilium caused by flowwithin the nephron tubule is detected by PC1 (orange) and PC2 (red), two transmembrane proteins. Flow induces Ca2+ influx through PC2and maintains STAT6 (yellow) and P100 (turquoise) in a complex bound to the tail of PC1. Flow also leads to up-regulation of Inversin(purple), which targets cytoplasmic Dsh (green) for degradation by the proteasome. (B) In the absence of flow, Ca2+ influx is reduced andthe tail of PC1 is cleaved, allowing P100 and STAT6 to translocate to the nucleus and activate transcription. Lack of flow also reducesInversin levels, stabilizing Dsh levels and permitting -catenin to initiate transcription of canonical Wnt pathway target genes. The samepathways may be activated in the absence of PC1, PC2, or the cilium itself, leading to unregulated cell proliferation and formation of cysts.


CILIOS PRIMARIOS EN OTRAS CLULAS

CILIOS NODALES

Receptor de somatostatina

Receptor de serotonina

CLULAS NEURALES


Singla & Reiter (2006). Science 313: 629-633.


Fig. 1. Primary cilia are highly structured and are found in many organisms and on many cell types.

V Singla, J F Reiter Science 2006;313:629-633

Published by AAAS


Figure 1. The ubiquity of cilia.

Marshall, WF & Nonaka, S (2006). Cilia: tuning in to the cells antenna. Curr Biol 16: R604-R614.


FORMACIN DEL CILIO PRIMARIO

Current Opinion in Cell Biology 2010, 22:541546

Rohatgi and Snell.


42

Regionalization of the nervous system:D-V axis determination by diffusible factors

time

As a result of induction, neurons at different D-V axis positions in the spinal cord adopt different fates

Bone morphogenetic proteins (BMPs) induce dorsal fatesAnd sonic hedgehog (SHH) induces ventral fates

Figure 52-5

As the neural tube forms, gradients of signaling factors are established along its D-V axis

Roof plate & epidermisFloor plate & notochord

Morphogen produces specific responses depending on its conc.


Especificacin del tubo neural ventral por Shh


Mutantes del sistema de transporte intraflagelar y los defectos asociados en las especificacin del tubo neural

Goetz et al (2009). The primary cilium as a hedgehog signal transduction machine . Methods Cell Biol 94: 199-122.


A model of vertebrate Hh signal transduction.V Singla, J F Reiter Science 2006;313:629-633

Published by AAAS

A model of vertebrate Hh signal transduction. (A) In the absence of Hh, Ptc (blue) represses the function of Smo(purple), which is predominantly on intracellular vesicles. Gli proteins are processed at the cilium into their transcriptional repressor forms (red). These repressors move down the cilium to the nucleus and bind regulatory elements to maintain the silence of the Hh transcriptional program. (B) In the presence of Hh proteins such as Shh(orange), the inhibition of Smo by Ptc is blocked and Smo moves to the cilium. There, it presumably interacts with the Gli processing machinery (yellow) to promote formation of transcriptional activator forms (green). Gli activators then enter the nucleus where they activate Hh-dependent transcription.


La va de sealizacin de Shh

The vertebrate Hedgehog (Hh) pathway in the absence (A) or presence (B) of Sonic hedgehog (Shh) ligand. (A) In the absence of ligand, the Shh receptor Ptch1 prevents the activation of another transmembrane domain protein, Smo. In this state, full length Gli2 and Gli3 are proteolytically processed into a smaller repressor form. (B) Upon Shh ligand binding to Ptch1, the inhibition on Smo is relieved and activates full-length Gli proteins and blocks productionof Gli repressors.Goetz et al (2009). The primary cilium as a hedgehog signal transduction machine . Methods Cell Biol 94: 199-122.


Localizacin de los componentes de la va de sealizacin Shh en el cilio primario



(A) In the absence of Shh ligand, Ptch1 is enriched in primary cilia and Smo is not. Sufu andGli are present at the cilia tip, and events take place that promote proteolytic processing of Gli3to the transcriptional repressor form (red star), causing repression of Hh target genes. KIf7, akinesin homologous to Drosophila Cos2, is present at the base of the cilium and helps preventactivation of the pathway. (B) In the presence of Shh ligand, Shh binds to Ptch1, and Ptch1moves out of the ciliary axoneme. In parallel, Smo is enriched in primary cilia and promotesactivation rather than proteolytic processing of Gli proteins. Kif7 moves from the base to thetips of cilia and contributes to the activation of Gli proteins. Activated Gli proteins aretransported out of the cilium to turn on Shh target gene expression in the nucleus. Sufu and Gliproteins are localized to the tip of the cilium in both the presence and absence of ligand, as isTulp3.



EL CILIO DESAPARECE DURANTE LA MITOSIS Y POSTERIORMENTE SE FORMA NUEVAMENTE


PERO. SIEMPRE DESAPARECE CUANDO LA CLULA ENTRA EN MITOSIS ?

EPITELIO UTERINO: normalmente no es ciliado debido al constante turnover. Sin embargo, luego de la ovarioctomia el epitelio uterino entra en quiescencia y es uniformemente ciliado.12 24 hs despus de la aplicacin de estradiol, las clulas pierden los cilios, los cuerpos basales y 24 hs despus casi todas entran en mitosis.


Pero, recordar clulas durante la embriognesis !!!!


QUIMIORECEPCIN EN EL CILIO A TRAVS DE CANALES INICOS

Lorenzo et al (2008) localizaron el receptor TRPV4 en clulas epiteliales respiratorias

Agonista de TRPV4


Dietrich J et al. (2008) Mechanisms of Disease: the role of stem cells in the biology and treatment of gliomasNat Clin Pract Oncol doi:10.1038/ncponc1132

Figure 2 Neural stem cells (NSCs) in the adult mammalian brain (SVZ, hippocampus)


Fig. 3 Schematic representation of fractones in the neural stem cell niche. Fractones (yellow) are laminin-rich structures continuous with the basal lamina (yellow) of blood vessels (bv). They project into the subventricular zone (SVZ) and terminate in tips closely associated with the multi-ciliated ependymal cells (e) lining the lateral ventricle. Fractones are in direct contact with the stem and progenitor cells of the SVZ shown in blue (type B cells), green (type C cells) and red (type A cells). In the neural stem cell niche shown here, Type A cells are proliferating neuroblasts migrating rostrally to the olfactory bulb while type C precursor cells are stationary yet rapidly dividing cells. Type B cells have astrocytic features and are considered the stem cells of the adult brain. They are dividing slowly and ensheath migrating type A cells with extensive cellular processes48. The presence of basal lamina and its proximity to the cells in the SVZ could provide a scaffold for HA in extracellular spaces. Retention of HA in the SVZ could in turn influence stem cell quiescence and HA processing upon external stimuli could induce stem cells to produce rapidly dividing progenitor cells.

Larry S. Sherman: Dr. Larry S. Sherman is a Senior Scientist in the Division of Neuroscience at the Oregon National Primate Research Center and an Associate Professor in the Department of Cell and Developmental Biology, in the Neuroscience Graduate Program, and in the Program for Molecular and Cellular Biology at the Oregon Health & Science University.

Kerstin Feistel: Dr. Kerstin Feistelis a postdoctoral fellow in the laboratory of Dr. Larry Sherman at Oregon Health and Science University.


Fig. 3. Cell migration defectsin the Tg737orpk mutant. (A andB) Whole mounts of the lateralwalls of the lateral ventriclestained with antibody againstPSA-NCAM. A well-organizedlongitudinal array of chains(arrowheads) was observed inthe wild-type brain (WT) (A)but not in the Tg737orpk/orpkmutant (B). Higher magnificationviews of the dorsal regionmarked by squares (A) and (B)are shown in the insets to theright. (C to E) Normal cilia arerequired for rostral migration ofendogenous neuroblasts. Sagittalsections of wild-type (C) andTg737orpk (D) olfactory bulbs 5days after injection of alkalinephosphataseencoding retrovirusinto the SVZ. (E) Thenumber of alkaline phosphatasecells (means T SD) reaching the olfactory bulb in the Tg737orpk/orpk mice was significantly smaller than in the wild type (P 0 0.0004, ttest). Total number of cells counted: wild type, 396 (n 0 3); mutant, 112 (n 0 3). (F) Tg737orpk/orpk mutant neuroblasts can migrate normally in thewild-type brain. SVZ cells from wild-type or Tg737orpk/orpk mutant mice carrying GFP were grafted into the SVZ of wild-type brains. (See fig. S4.) Thehistogram shows the number of GFP cells (means T SD) in the olfactory bulbs 5 days (n 0 4) and 16 days (n 0 4) after transplantation. Nosignificant difference was observed (P 0 0.7763 at day 5 and 0.422 at day 16, t test). (G) Wild-type neuroblasts failed to migrate normally in theTg737orpk/orpk mutant brain. GFP-labeled SVZ cells from wild-type mice were grafted into the SVZ of wild-type and Tg737orpk/orpk mutant mice. (Seefig S4.) The histogram shows the number of GFP cells in the olfactory bulbs 5 days after transplantation (means T SD) (n 0 4). The number of wildtypecells reaching the olfactory bulb in the Tg737orpk/orpk brain was significantly smaller than in the wild type to wild type transplantation controls


cilios - bc

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