The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis

Cheerambathur, Dhanya K.; Prevo, Bram; Chow, Tiffany-Lynn; Hattersley, Neil; Wang, Shaohe; Zhao, Zhiling; Kim, Tae‐Kyung; Gerson-Gurwitz, Adina; Oegema, Karen; Green, Rebecca A.; Desai, Arshad

doi:10.1016/j.devcel.2019.02.002

Cited by 41 publications

(69 citation statements)

References 40 publications

(53 reference statements)

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“…We hypothesize that post-translational modifications in the amino-terminal domain of Spindly may regulate its role in neurodevelopment. Recently it has been reported that other kinetochore proteins are important for neurodevelopment (30, 31) [reviewed in (32)]. For example, depletion of Mis12, Knl1 and Ndc80 (other kinetochore components) results in abnormal neuromuscular junctions and central nervous system development both in Drosophila and in C. elegans (30, 31).…”

Section: Discussionmentioning

confidence: 99%

Kinetochore protein Spindly controls microtubule polarity inDrosophilaaxons

Castillo¹,

Müller

Gelfand³

2020

Preprint

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24Microtubule polarity in axons and dendrites defines the direction of intracellular transport 25 in neurons. Axons contain arrays of uniformly polarized microtubules with plus-ends 26 facing the tips of the processes (plus-end-out), while dendrites contain microtubules with 27 minus-end-out orientation. It has been shown that cytoplasmic dynein, targeted to cortical 28 actin, removes minus-end-out microtubules from axons. Here we have identified Spindly, 29 a protein known for recruitment of dynein to kinetochores in mitosis, as a key factor 30 required for dynein-dependent microtubule sorting in axons of Drosophila neurons. 31Depletion of Spindly affects polarity of axonal microtubules in vivo and in primary neuronal 32cultures. In addition to these defects, depletion of Spindly in neurons causes major 33 collapse of axonal patterning in the third-instar larval brain as well as severe coordination 34 impairment in adult flies. These defects can be fully rescued by full-length Spindly, but 35 not by variants with mutations in its dynein-binding site. Biochemical analysis 36 demonstrated that Spindly binds F-actin, suggesting that Spindly serves as a link between 37 dynein and cortical actin in axons. Therefore, Spindly plays a critical role during 38 neurodevelopment by mediating dynein-driven sorting of axonal microtubules. 39 40 Significance Statement 41Neurons send and receive electrical signals through long microtubule-filled neurites called 42 axons and dendrites. One of the main structural differences between axons and dendrites 43 is how their microtubules are organized. Axons contains microtubules with their plus-ends 44 out while microtubules in dendrites are organized with mixed or plus-end-in orientation. 45Dynein, the main minus-end microtubule motor, anchored to cortical actin filaments in the 46 axons is responsible for the uniform microtubule polarity in axons. However, it is unknown 47 how dynein is recruited to the actin cortex in axons. The major finding of this work is that 48Spindly, a protein involved in anchoring dynein to kinetochores during cell division, has a 49 second important function in interphase cells recruiting dynein to the actin cortex in axons. 50 51 Introduction 52Neurons are post-mitotic cells that transmit electrical signals through long neurites called 53 axons and dendrites. Electric signals captured by dendrites are sent unidirectionally 54 through axons and transmitted to other cells. The polarity of microtubules is strikingly 55 different in these two types of neuronal processes. Axons contain microtubules oriented 56 predominantly with their plus-ends-out, while dendrites contain a large fraction of minus-57 end-out microtubules (1, 2). Failure in establishing correct polarity of microtubules results 58 in defects of cargo sorting (3). The differences in microtubule orientation between axons 59 and dendrites are gradually established during development. In cultured early stage 60 neurons, non-polarized neurites contain microtubules with mixed orientation. Later the 61...

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Section: Discussionmentioning

confidence: 99%

Kinetochore protein Spindly controls microtubule polarity inDrosophilaaxons

Castillo¹,

Müller

Gelfand³

2020

Preprint

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“…Lastly, in C. elegans, Drosophila, and iPS-derived human motor neurons, some or all of the core kinetochore proteins localize to the regions of synaptic neuropil and axons that are devoid of nuclei. There they control axon outgrowth and dendritic extension in the developing sensory nervous system (Cheerambathur et al 2019;Zhao et al 2019). All of these examples highlight that the timing and location of kinetochore assembly are tuned to the cell cycle and cell type.…”

Section: Cells Customize Kinetochore Activity By Controlling Kinetochmentioning

confidence: 99%

Aurora B-dependent Ndc80 degradation regulates kinetochore composition in meiosis

et al. 2020

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The kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We previously described the regulatory events that control the timely synthesis of Ndc80. Here, we report that Ndc80 turnover is also tightly regulated in meiosis: Ndc80 degradation is active in meiotic prophase, but not in metaphase I. Ndc80 degradation depends on the ubiquitin ligase APC Ama1 and is mediated by the proteasome. Importantly, Aurora B-dependent Ndc80 phosphorylation, a mark that has been previously implicated in correcting erroneous microtubule-kinetochore attachments, is essential for Ndc80 degradation in a microtubule-independent manner. The N terminus of Ndc80, including a 27-residue sequence and Aurora B phosphorylation sites, is both necessary and sufficient for kinetochore protein degradation. Finally, defects in Ndc80 turnover predispose meiotic cells to chromosome mis-segregation. Our study elucidates the mechanism by which meiotic cells modulate their kinetochore composition through regulated Ndc80 degradation, and demonstrates that Aurora B-dependent regulation of kinetochores extends beyond altering microtubule attachments.

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“…32). For example, depletion of Mis12, Knl1, and Ndc80 (other kinetochore components) results in abnormal neuromuscular junctions and central nervous system development both in Drosophila and in Caenorhabditis elegans (30,31). However, the precise roles of these kinetochore proteins in neurodevelopment are as yet unknown.…”

Section: Discussionmentioning

confidence: 99%

Kinetochore protein Spindly controls microtubule polarity in Drosophila axons

Castillo¹,

Müller

Gelfand³

2020

Proc. Natl. Acad. Sci. U.S.A.

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Microtubule polarity in axons and dendrites defines the direction of intracellular transport in neurons. Axons contain arrays of uniformly polarized microtubules with plus-ends facing the tips of the processes (plus-end-out), while dendrites contain microtubules with a minus-end-out orientation. It has been shown that cytoplasmic dynein, targeted to cortical actin, removes minus-end-out microtubules from axons. Here we have identified Spindly, a protein known for recruitment of dynein to kinetochores in mitosis, as a key factor required for dynein-dependent microtubule sorting in axons ofDrosophilaneurons. Depletion of Spindly affects polarity of axonal microtubules in vivo and in primary neuronal cultures. In addition to these defects, depletion of Spindly in neurons causes major collapse of axonal patterning in the third-instar larval brain as well as severe coordination impairment in adult flies. These defects can be fully rescued by full-length Spindly, but not by variants with mutations in its dynein-binding site. Biochemical analysis demonstrated that Spindly binds F-actin, suggesting that Spindly serves as a link between dynein and cortical actin in axons. Therefore, Spindly plays a critical role during neurodevelopment by mediating dynein-driven sorting of axonal microtubules.

show abstract

The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis

Cited by 41 publications

References 40 publications

Kinetochore protein Spindly controls microtubule polarity inDrosophilaaxons

Kinetochore protein Spindly controls microtubule polarity inDrosophilaaxons

Aurora B-dependent Ndc80 degradation regulates kinetochore composition in meiosis

Kinetochore protein Spindly controls microtubule polarity in Drosophila axons

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