Abstract
Neurons require a well-coordinated intercellular transport system to maintain their normal cellular function and morphology. The kinesin family of proteins (KIFs) fills this role by regulating the transport of a diverse array of cargos in post-mitotic cells. On the other hand, in mitotic cells, KIFs facilitate the fidelity of the cellular division machinery. Though certain mitotic KIFs function in post-mitotic neurons, little is known about them. We studied the role of a mitotic KIF (KIF3B) in neuronal architecture. We find that the RNAi mediated knockdown of KIF3B in primary cortical neurons resulted in an increase in spine density; the number of thin and mushroom spines; and dendritic branching. Consistent with the change in spine density, we observed a specific increase in the distribution of the excitatory post-synaptic protein, PSD-95 in KIF3B knockdown neurons. Interestingly, overexpression of KIF3B produced a reduction in spine density, in particular mushroom spines, and a decrease in dendritic branching. These studies suggest that KIF3B is a key determinant of cortical neuron morphology and that it functions as an inhibitory constraint on structural plasticity, further illuminating the significance of mitotic KIFs in post-mitotic neurons.
Highlights
Neurons are senescent, multipolar cells that require specialized transport machinery to maintain normal cellular function, and morphology
Since genetic studies have suggested that KIF3B functions in cell division and early development, to assess the role of KIF3B in post-mitotic neurons, we considered RNAi mediated loss of function experiments
Consistent with the spine density data, we observed an enrichment in the number of mushroom and thin spines; no change in stubby spines was observed (Figure 2D; Mushroom spines: shKIF3B 20.28 ± 2.07, shScrambled 13.14 ± 1.78, Student’s t-test, t(56) = 2.596, ∗p < 0.05; Thin spines: shKIF3B-A 26.58 ± 1.65, shScrambled 13.81 ± 1.59, Student’s t-test, t(56) = 5.546, ∗∗∗∗p < 0.0001; Stubby spines: shKIF3B-A 4.23 ± 1.14, shScrambled 5.91 ± 1.00, Student’s t-test, t(56) = 1.094, ns. p > 0.05). These results indicate that KIF3B is a negative regulator of spine density and spine morphology of cortical pyramidal neurons
Summary
Multipolar cells that require specialized transport machinery to maintain normal cellular function, and morphology. Molecular motor proteins known as the kinesin family of proteins (KIFs) are vital players in this intracellular transport system in post-mitotic neurons. KIFs use ATP hydrolysis to generate force to bind and move along the microtubule (MT) cytoskeleton to transport cargos of RNA, organelles, and proteins to distal areas of the cell (Hirokawa, 1998; Puthanveettil et al, 2008; Puthanveettil, 2013). KIF function can be separated into two broad groups based on the cell types in which it is localized: modulation of the cytoskeleton in mitotic cells and trafficking of cargos in post-mitotic cells. Several KIFs have been shown to facilitate cell division by aiding the movement of machinery required for cytokinesis as well as transporting mitotic specific cargos.
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