THE ROLE OF INTEGRIN ADHESIONS IN AXON GROWTH

  • Cristina Melero

Student thesis: Phd

Abstract

Axons are the slender cable-like extensions of neurons wiring the nervous system. They initially grow guided towards the correct destinations by motile devices at their tips called growth cones (GC), which display receptors on their surfaces to detect chemical and physical cues in the neuronal environment, and translate them into directional movements. Once synapses with target cells are formed, axon shafts elongate further through intercalative growth to adapt to increases in body size. Axon growth and the underlying regulated shape changes and locomotion involve (1) cytoskeletal dynamics requiring the coordinated dynamics and cross-talk of acto-myosin and microtubules (MTs); (2) adhesions to establish physical links to the environment and sense its physical properties, and (3) signalling mechanisms to incorporate information from guidance cues in the environment. All of these aspects contribute to the generation and regulation of the forces that make an axon grow. The fundamental question of whether axon growth is implemented through the pulling of GCs on axon shafts or through pushing forces generated in axon shafts and controlled and guided by GCs, remains unresolved. To address this question, I have used Drosophila primary neurons as a powerful, evolutionary well conserved model, already providing excellent means to study cytoskeleton and signalling contributions. Here I introduced experimentation on adhesions to this model. I found that ECM harvested from Drosophila Kc cell lines (dECM) causes a strong increase in axon growth and reduces GC sizes. These changes do not require dystroglycan or syndecan but the laminin receptor αPS1/βPS integrin and its actin linker talin. Key downstream events are (1) the down-regulation of acto-myosin activity and (2) an increase in MT polymerisation velocities. The downstream mechanisms regulating MT behaviours seem to imply integrin-linked kinase (Ilk) and Kank, whereas it is not clear if paxillin works downstream of integrins or in an independent pathway. Also potential RhoA links from integrins to acto-myosin regulation turn out to be very complex and might involve further Rho GTPaes. I propose that pushing forces generated along the axon shaft via net plus MT polymerisation are key drivers of axon growth, whereas GCs slow down growth required for decision making but do not actively pull on the axon to stimulate extension. In agreement with this model, I find a negative correlation between GC area and axon length, and that larger GCs generate larger traction forces which seem therefore to translate into growth inhibition rather than acceleration. The comprehensive studies possible in Drosophila and reflected in my work provide new opportunities to develop integrated models of axon growth.
Date of Award31 Dec 2018
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAndreas Prokop (Supervisor) & Christoph Ballestrem (Supervisor)

Keywords

  • forces
  • integrins
  • adhesions
  • cytoskeleton
  • growth cone
  • axon
  • neuron
  • axon growth

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