Cell and Developmental BiologyMicrotubule organization

Microtubule organization

Candidates with a strong interest in the microtubule cytoskeleton who would like to join our group should e-mail a cover letter with CV including contact information for references to jens.ludersirbbarcelona.org.

MTOCs, γTuRCs, and microtubule nucleation

Assembly of ordered microtubule arrays involves microtubule organizing centers (MTOCs), which nucleate microtubule polymerization and control attachment and release of microtubules. A well-known MTOC in animal cells is the centrosome. The centrosome consists of a pair of centrioles that is surrounded by the so-called pericentriolar material (PCM). The centrioles, barrel-shaped cylinders composed of precisely arranged triplets of short microtubules and other proteins, have an important role in maintaining a single centrosome per cell, but are not directly involved in the nucleation of microtubules. Nucleation occurs within the PCM and requires γ-tubulin. Together with additional proteins γ-tubulin forms multi-subunit γ-tubulin ring complexes (γTuRCs), which are the main microtubule nucleators at centrosomes and other MTOCs. How γTuRC subunits interact with each other to assemble γTuRCs is poorly understood.

microtubule nucleation

Microtubule nucleation at centrosomes. (A)The animal centrosome is composed of a pair of centrioles (mother centriole with distal and subdistal appendages, daughter centriole) surrounded by PCM. γTuRCs in the PCM nucleate microtubules. (B) Purified γTuRC displays the typical ~25nm diameter ring shape when analyzed by electron microscopy. (C) γTuRC nucleates microtubule polymerization by providing a template for the assembly of α-β-tubulin heterodimers (template nucleation model).

Proper organization of microtubule requires nucleation to be regulated. Different levels of regulation exist. Targeting factors mediate interaction of γTuRC with MTOCs to restrict nucleation spatially. Other interactors might activate γTuRC nucleation activity. An additional level of regulation is provided by kinases that phosphorylate γTuRC subunits. The molecular details of γTuRC regulation are unclear mainly because we lack insight into γTuRC structure and how it is linked to the nucleation mechanism.

Microtubule organization and disease

During mitosis centrosomes organize microtubules at the poles of the mitotic spindle. Abnormal centrosome number and function have been implicated in genomic instability, cancer development and progression, and are common in tumor cells. During metastasis the microtubule cytoskeleton has roles in cell morphogenesis, invasion, and migration. As organizers of mitotic spindle poles centrosomes are also important for asymmetric stem cell divisions. For example, defects in certain genes encoding centrosome- and spindle-associated proteins cause microcephaly, a disorder of neurogenic mitosis that results in reduced fetal brain growth. Neurons form long cellular processes and have to transport cargo over very long distances. Therefore neurons are particularly sensitive to perturbations of the microtubule network. Impaired microtubule-based transport can lead to neurodegeneration and may also have a role in the pathologies observed in Parkinson’s and Alzheimer’s disease.

Microtubule-dependent processes such as intracellular transport, cell motility and segregation of chromosomes during mitotic and meiotic divisions, require microtubules to be organized into highly ordered arrays. Failure to properly organize spindle microtubules during mitosis, for example, has been implicated in genomic instability and cancer. In addition, defects in components of the microtubule cytoskeleton are the cause of various developmental and degenerative disorders. The overall goal of our lab is a molecular understanding of how cells generate and remodel distinct types of microtubule arrays during cell cycle progression and during cell differentiation, and how errors are linked to disease. We study these processes in cultured primary cells and cell lines, and by in vitro reconstitution using purified proteins and extract prepared from eggs of the frog Xenopus laevis.

organization-microtubules

Organization of the microtubule cytoskeleton. The distribution of microtubule organizing centers (MTOCs; green) and the geometry of microtubule arrays (red) are variable and depend on cell cycle stage and cell type. Nuclei are shown in blue.

i) Provide mechanistic insight into microtubule nucleation

  • structure, function and regulation of the γ-tubulin ring complex (γTuRC)

ii) Elucidate how microtubule nucleation contributes to spindle assembly and remodeling during mitosis

  • centrosomal and non-centrosomal mechanisms of microtubule nucleation
  • regulation by mitotic kinases

iii) Study how protein phosphorylation, alongside other signals such as the Ran(GTP) gradient, control the centrosomal and microtubule machinery during G2 and mitosis (with Joan Roig, see http://nek9.wordpress.com/)

  • NIMA-family of protein kinases and their relationship to other mitotic signaling systems
  • the Nek9/Nek6/7 signaling module during cellular transformation and its possible interest as a therapeutic target

iV) Study microtubule organization in non-mitotic cells in the context of development and disease

  • neurodevelopment and -degeneration
  • invasive and migratory cell behavior
Cota RR, Teixidó-Travesa N, Ezquerra A, Eibes S, Lacasa C, Roig J and Lüders J.
J Cell Sci, 130 (2), 406-419 (2017)
Sánchez-Huertas C, Freixo F, Viais R, Lacasa C, Soriano E and Lüders J.
Nat Commun, 7 12187 (2016)
Marjanović M, Sánchez-Huertas C, Terré B, Gómez R, Scheel JF, Pacheco S, Knobel PA, Martínez-Marchal A, Aivio S, Palenzuela L, Wolfrum U, McKinnon PJ, Suja JA, Roig I, Costanzo V, Lüders J and Stracker TH.
Nat Commun, 6 7676 (2015)
Sánchez-Huertas C and Lüders J.
Curr Biol, 25 (7), R294-9 (2015)
Lecland N and Lüders J.
Nat Cell Biol, 16 (8), 770-8 (2014)
Comartin D, Gupta GD, Fussner E, Coyaud E, Hasegan M, Archinti M, Cheung SW, Pinchev D, Lawo S, Raught B, Bazett-Jones DP, Lüders J and Pelletier L.
Curr Biol, 23 (14), 1360-6 (2013)
Lüders J.
Nat Cell Biol, 14 (11), 1126-8 (2012)
Teixidó-Travesa N, Roig J and Lüders J.
J Cell Sci, 125 (Pt 19), 4445-56 (2012)
Teixidó-Travesa N, Villén J, Lacasa C, Bertran MT, Archinti M, Gygi SP, Caelles C, Roig J and Lüders J.
Mol Biol Cell, 21 (22), 3963-72 (2010)

This group is financially supported by the following:

  • Ministerio de Economía y Competitividad (MINECO)
  • European Commission (EC), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa"

     

Group news & mentions

22 Jul 2016

Amplia cobertura mediática del trabajo de Jens Lüders del Laboratorio de Organización Microtubular sobre un nuevo mecanismo con el cual las neuronas mantienen y regeneran sus axones.

<p>Microscopy image of a culture mouse neuron showing the microtubule network in green and red depending on chemical modifications. The axon, in bright green, is the neuronal extension that has the greatest number of modified microtubules (Author: Carlos Sán</p>
21 Jul 2016

Científicos del Instituto de Investigación Biomédica (IRB Barcelona) liderados por Jens Lüders, investigador principal del laboratorio de

<p>CEP63 depletion increases stem cell death in the developing mouse brain. The image on the right shows the stem dying cells in purple. The mice are born with microcephaly, a characteristic feature of Seckel Syndrome (Image: Berta Terré, IRB Barcelona)</p>
7 Jul 2015

Investigadores del Instituto de Investigación Biomédica (IRB Barcelona) ofrecen en la revista Nature Communications detalles moleculares del Síndrome de Seckel, una enfermedad de las denom

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