Regulation of Cytokinesis in Neural Stem Cells During Cerebral Cortex Development 382 views

Mammalian brains have an expanded cerebral cortex, which is essential for many of the processes we consider to be innately human, like consciousness and language. The cerebral cortex contains six layers of neurons that are all derived from the expansion of neural stem cells (NSCs). The neurons within these layers are polarized cells with unique morphologies. The fate decisions that occur during cell division of NSCs to produce specific neurons for each layer is still under intense investigation. NSCs must make these fate decisions at the correct time during development to produce an exact number of neurons. Errors in neuron production cause developmental disorders like microcephaly. How NSCs can control this cell fate process is still quite mysterious. The coordination of many different processes most likely controls cell fate decisions. In this thesis, we will focus on one cell cycle process, cytokinesis. Cytokinesis, the separation of two daughter cells, can be split into cleavage furrowing and abscission. We will focus on two critical proteins that localize to the midbody during abscission, Kif20b and Cep55. The loss of either of these proteins causes problems with NSC divisions and mouse mutants with small brains. This highlights the importance of regulated NSC cytokinesis for developing a correctly sized and correct structure cortex. This thesis work furthers our understanding of cytokinesis within the developing cerebral cortex, and the role of two midbody proteins Kif20b and Cep55. We have found that abscission duration and midbody remnant disposal is regulated developmentally. The loss of Kif20b in cell lines causes dysregulated cleavage furrowing and abscission, as well as disrupted ESCRT recruitment. When Kif20b is lost in NSCs, abscission is faster, and there is p53-independent early neurogenesis. Kif20b also affects neuron polarization and outgrowth. Without Cep55 in NSCs, these cells have disrupted cytokinesis. These data, taken together, show that slight perturbations from the loss Kif20b or Cep55 cause dysregulated cytokinesis and influence overall brain development. Both proteins are expressed in other cell types, but the brain is the most severely perturbed. This highlights the essential role regulated cytokinesis and midbody remnant disposal play in cerebral cortex development.

PHD (Doctor of Philosophy)

Neural Stem Cells; Cytokinesis; Microcephaly; Cerebral Cortex; Cytokinetic Abscission

English

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2020-04-14