From Genes to Circuits: Molecular Regulation of Dopamine Neuron Development

Abstract

The interaction of a myriad of molecular factors is necessary for proper development of mDA circuitry. Although significant progress has been made in uncovering the mechanisms involved in mDA neuron development, our understanding of the role played by specific classes of molecules (such as non-coding RNAs) is still incomplete. To extend existing knowledge, we examined the cellular aspects of mDA neuron development (chapter 1). Using this information, we identified relevant timepoints for a comprehensive transcriptomic profiling study of mouse mDA neurons and employed bioinformatics analysis to uncover patterns of lncRNA and circRNA expression during embryonic and postnatal development (chapter 1). We selected specific circRNA candidates for further functional investigation (chapter 2). Through in vitro and in vivo knockdown of a particular circRNA, we discovered several cellular and molecular changes in normal mDA neuron development.

Advances in sequencing techniques have facilitated the assessment of molecular profiles at the single-cell level in a more efficient and rapid manner. However, the definition of subtypes remains a subject of debate. Therefore, to gain a better understanding of the extent of mDA system heterogeneity, it is crucial to study cellular properties, such as morphology and electrophysiology. Consequently, we utilized intersectional mouse genetics to investigate different subsets of mDA neurons and their individual morphology (chapter 3).

The mDA system can be broadly categorized into the VTA and the SNc. These two regions receive and respond to distinct molecular signals that guide the neurons to their final positions after birth. In chapter 4, we made a novel discovery regarding a long-range mechanism that promotes cellular migration. Furthermore, we demonstrate the importance of the localization of other cell types (specifically, GABAergic neurons) for the proper placement of mDA neurons.