Genetic Control of Rodent Midbrain Dopaminergic Neuron Development in the Light of Human Disease

Abstract

Dopamine-producing neurons in the mammalian midbrain have received considerable attention in recent years because of their involvement in diverse neurological and psychiatric human disorders such as Parkinson's Disease (PD), schizophrenia and addiction. Although the underlying pathogenic mechanisms of these disorders are far from being understood, it is meanwhile accepted that a combination of genetic predisposition and environmental factors lead to the disease state. More recent evidence also suggests that both neurological and psychiatric disorders result from early disturbances affecting the normal development of the mesencephalic dopaminergic (mesDA) neurons. Understanding the cues directing the generation of the different mesDA cell groups, the establishment of their proper connections within the brain and their maintenance in the adult are therefore also of great clinical interest. Rodents, and in particular the mouse, have served as the classical "surrogate" organism for these studies based on their phylogenetic relationship to humans, their relatively well characterized mesDA system on both the anatomical and physiological levels, and especially on the propensity of the mouse to genetic manipulation enabling the dissection of genetic pathways underlying the proper generation and maintenance of the mesDA system in this species. In the present review, we will summarize recent findings in the overall context of murine mesDA neuron development.

Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha‐6 chain as a novel regulator of striatal axonal branching in mice

“…While DA neurons residing in the SN are of central interest to translational neuroscience research because of their unique properties that renders them susceptible in PD, 59 many factors modulating their properties remain unknown. Uncovering factors that control their development, structure, and function help understand how they interrelate with other nervous system components in assuring the proper operations of the brain, or how they contribute to disease 9 …”

“…Age of onset, severity, rate of progression of PD motor symptoms, as well as the response to DA replacement therapies, vary greatly and are likely because of polymorphism in genes of the nigrostriatal circuit 7,8 . Genetic factors governing the development of this circuit and its baseline functions in adults are frequently those that are dysregulated in PD 9 . Hence, a better understanding of genetic variation associated with these factors could pave the way for a better understanding of PD.…”

Progesterone Increases Dopamine Neurone Number in Differentiating Mouse Embryonic Stem Cells

“…Recently, we have shown (44) that oestradiol, in the presence of 20 n m progesterone, during stage 4 increases the proportion of proliferating dopamine precursors by assessing the expression of Lmx1a (a transcription factor present in committed dopamine cells) and Ki67 (an antigen present in cells with active cell cycle), resulting in higher number of dopamine neurones. In future studies, an investigation of the intracellular effectors responsible for the up‐regulation of dopamine‐related transcription factors (45, 46) after progesterone treatment might lead to a better understanding of dopamine neurone differentiation.…”

Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models

“…Fgf 8 is secreted from the rostral hindbrain early in development and is essential for the orderly formation of the boundary between mid and hind-brain. 107 In particular, it would appear that fgf 8 is essential for the proper positioning of mitotic cells within this region many of which will become dopaminergic. 78 Nurr1 is an obligatory factor in msDA neuron development and maturation.…”