Catenin-β1 Programs Neural Self-organisation

Abstract

Self-organisation describes emergence of global order from local interactions between components of a system without supervision by external directing forces.This decentralised mode of decision making is central to social phenomena such as swarm behaviour in bacteria, flocking of birds, and schooling of fish. Biological self-organisation also governs morphogenic dynamics during development of multi-cellular organisms. By self-organisation, dichotomies such as proliferation/differentiation are resolved based on simple interactions of cells. During neural morphogenesis, for example, self-organisation cues instruct temporal commitment to differentiation of neural progenitor cells and sub-lineage differentiation outcomes. In this thesis, the identity of molecular switches that orchestrate human neural self-organisation is investigated. In the first data chapter, a primary cellular model of human adult neurogenesis is developed that is not confounded by noise inherent to cell lines. The model is based on direct trans-differentiation of human microvascular pericytes to functional interneurons without exogenous interference. Due to lack of transitional cellular forms, such as transient amplifying cells, the model system demonstrated minimal temporal noise and high fidelity. In the second data chapter of the thesis, the signalling activity of a novel morphogenic microRNA is described that can access and override the self-organisation program of human neural progenitors. The microRNA interacts with an ancient cascade involved in detection of metabolic stressors. By downregulating a key component of the cascade, cdk-18,the miRNA invokes a faux stress response that impacts upon availability of free-cytoplasmic catenin-β1 and synchronises the cycling neural progenitors and also instructs their differentiation fate. In the third data chapter, evolutionary origin of the microRNA is investigated in order to gain insight into the interface of the microRNA and Wnt/catenin-β1 signalling cascades during emergence of self-organisation. Finally, in the last data chapter it is demonstrated that catenin-β1 encodes the self-organisation lexicon of human neural progenitors by coupling the cell cycle of individual cells. By manipulating the subcellular localisation of catenin-β1 and hence the strength of coupling, spatial organisation and differentiation propensity of neural progenitors is reprogrammed.