During the past decade enormous advances have been made in our understanding of the basic molecular machinery that is involved in the development of neuronal polarity. Far from being mere structural elements, microtubules are emerging as key determinants of neuronal polarity. Here we review the current understanding of the regulation of microtubule assembly, organization and dynamics in axons and dendrites. These studies provide new insight into microtubules' function in neuronal development and their potential contribution to plasticity.

Microtubule assembly, organization and dynamics in axons and dendrites.

Microtubule plus-end tracking proteins (+TIPs) are a diverse group of evolutionarily conserved cellular factors that accumulate at the ends of growing microtubules. They form dynamic networks through the interaction of a limited set of protein modules, repeat sequences and linear motifs that bind to each other with moderate affinities. +TIPs regulate different aspects of cell architecture by controlling microtubule dynamics, microtubule interactions with cellular structures and signalling factors, and the forces that are exerted on microtubule networks.

Tracking the ends: a dynamic protein network controls the fate of microtubule tips

https://www.jbc.org/content/277/7/4589.full.pdf

Signaling properties of hyaluronan receptors.

ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin.

An important function of microtubules is to move cellular structures such as chromosomes, mitotic spindles and other organelles around inside cells. This is achieved by attaching the ends of microtubules to cellular structures; as the microtubules grow and shrink, the structures are pushed or pulled around the cell. How do the ends of microtubules couple to cellular structures, and how does this coupling regulate the stability and distribution of the microtubules? It is now clear that there are at least three properties of a microtubule end: it has alternate structures; it has a biochemical transition defined by GTP hydrolysis; and it forms a distinct target for the binding of specific proteins. These different properties can be unified by thinking of the microtubule as a molecular machine, which switches between growing and shrinking modes. Each mode is associated with a specific end structure on which end-binding proteins can assemble to modulate dynamics and couple the dynamic properties of microtubules to the movement of cellular structures.

Dynamics and mechanics of the microtubule plus end

Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts.

The tandemly organised ribosomal DNA (rDNA) repeats are transcribed by a dedicated RNA polymerase in a specialised nuclear compartment, the nucleolus. There appears to be an intimate link between the maintenance of nucleolar structure and the presence of heterochromatic chromatin domains. This is particularly evident in many large neurons, where a single nucleolus is present, which is separated from the remainder of the nucleus by a characteristic shell of heterochromatin. Using a combined fluorescence in situ hybridisation and immunocytochemistry approach, we have analysed the molecular composition of this highly organised neuronal chromatin, to investigate its functional significance. We find that clusters of inactive, methylated rDNA repeats are present inside large neuronal nucleoli, which are often attached to the shell of heterochromatic DNA. Surprisingly, the methylated DNA-binding protein MeCP2, which is abundantly present in the centromeric and perinucleolar heterochromatin, does not associate significantly with the methylated rDNA repeats, whereas histone H1 does overlap partially with these clusters. Histone H1 also defines other, centromere-associated chromatin subdomains, together with the mammalian Polycomb group factor Eed. These data indicate that neuronal, perinucleolar heterochromatin consists of several classes of inactive DNA, that are linked to a fraction of the inactive rDNA repeats. These distinct chromatin domains may serve to regulate RNA transcription and processing efficiently and to protect rDNA repeats against unwanted silencing and/or homologous recombination events.

/pdf/characterisation-of-transcriptionally-active-and-inactive-28zo09ffr6.pdf

Characterisation of transcriptionally active and inactive chromatin domains in neurons.

https://repub.eur.nl/pub/8801/9535899.pdf

Ton Verkerk

Papers

Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts.

Characterisation of transcriptionally active and inactive chromatin domains in neurons.

The Centromeric/Nucleolar Chromatin Protein ZFP-37 May Function to Specify Neuronal Nuclear Domains

Amphotropic retroviruses with a hybrid long terminal repeat as a tool for gene therapy of cystic fibrosis