Abstract
Development and function of mesodiencephalic dopaminergic (mdDA) neurons has received a lot of scientific interest since these neurons are critically involved in neurological diseases as Parkinson and psychiatric diseases as schizophrenia, depression and attention deficit hyperactivity disorder (ADHD). The understanding of the molecular processes that lead to normal development and function of mdDA neurons has provided insight in the pathology and provided critical information on new treatment paradigms. In order to be able to study specific genetic ablation in mdDA neurons a new tools was developed that drives Cre-recombinase under the control of the Pitx3 locus. The Pitx3 gene is well known for its specific expression in mdDA neurons and is present at the onset of terminal differentiation. Analysis of newly generated Pitx3-Cre knock-in mice shows that Cre expression, measured through the activation of eYfp by removal of a “Stop” signal (LoxP-Stop-LoxP-eYfp reporter mouse), is present at the onset of terminal differentiation and mimics closely the native Pitx3 expression domain. In conclusion, we present here a new Cre-driver mouse model to be used in the restricted ablation of interesting genes in mdDA neurons in order to improve our understanding of the underlying molecular programming.
Highlights
Mesodiencephalic dopaminergic neurons are involved in voluntary movement control and regulation of emotion related behavior and are affected in many neurological and psychiatric disorders
There is an enormous interest towards the understanding of the molecular programming of Mesodiencephalic dopaminergic (mdDA) neurons from a clinical perspective and more fundamental perspective
The former as a tool to generate these neurons for cell-replacement therapy in the treatment of Parkinson’s disease (PD) and the latter as a model for molecular programing of neuronal systems in the vertebrate central nervous system (CNS)
Summary
Mesodiencephalic dopaminergic (mdDA) neurons are involved in voluntary movement control and regulation of emotion related behavior and are affected in many neurological and psychiatric disorders. The important link between the mdDA neurons in human CNS disorders and behavioral dysfunction has led to the intense study of this neuronal group in pharmacology and more recently in developmental neurobiology The former has led to the generation of many pharmacological intervention strategies to alleviate disease symptoms whereas the latter has provided general insight into the origin of the disease and the molecular mechanisms that define mdDA development, physiology and its failure in human pathology. We report on the generation of a mouse model that is designed to be able to induce Cre-recombinase in these mdDA neurons To achieve this goal we generated a knock-out/knock-in construct in the Pitx locus, a homeobox transcription factor well known for its involvement in mdDA development and for its restricted expression in time (onset of terminal differentiation) and place in these neurons [8,9,10,11,12]. The resulting eYfp expression in the adult system covers all mdDA neurons, making it an efficient and reliable tool for the ablation of genes of interest to the development of these neurons
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