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Defining the Molecular and Functional Diversity of Stem Cell-Derived Motor Neurons


Spinal motor neurons (MNs) are a diverse group of specialized neurons that innervate and control all muscles of the body, thereby allowing locomotion and respiration. Over the past decade, many groups have used directed differentiation of pluripotent stem cells into MNs to model human MN development and disease in vitro. Despite these efforts, it remains unknown whether stem cell-derived MNs fully recapitulate endogenous MN populations. To address this question, this thesis presents the characterization of human embryonic and stem cell-derived MNs on molecular and physiological levels. We find that the processes of MN development and organization are largely conserved between mice and humans. However, the majority of stem cell-derived MNs only express characteristics of MNs that normally innervate axial muscles in vivo. To expand the diversity of stem cell-derived MNs, we propose an alternative method of differentiation using overexpression of MN fate determinants. Specifically, we find that overexpression of the transcription factor Foxp1 during stem cell differentiation results in a large number of dorsal and ventral limb-innervating MNs. Finally, we demonstrate that stem cell-derived MNs are capable of forming functional synapses with muscle cells in vitro. Together, this work provides a detailed analysis of the strengths and weaknesses of current MN differentiation protocols, and presents new approaches for increasing the functional diversity of stem cell-derived MNs. In addition to valuable insights into human development, this body of work provides important information for ongoing efforts of modeling MN disease with stem cells.

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