Name Maria Teresa Miranda Alves dos Santos
Department Neuroscience and pharmacology
Section Neurodevelopment
FunctionPhD-student
E-mail:
m.t.m.alvesdossantos@umcutrecht.nl Tel +31 88 7568828
Supervisor Marten Smidt
Title research Find the function of the pitx3 and engrailed1 proteins in the mesDA system
Summary research The mesodiencephalic dopaminergic (mdDA) system is involved in the control of movement and behavior. These neurons are located in three distinct nuclei in the midbrain, one of which is the substantia nigra pars compacta (SN). The loss of dopaminergic neurons in this neuronal population is the neuropathological hallmark of Parkinson’s disease (PD). The homeobox transcription factors engrailed 1 (En1) and Pitx3 are expressed in the SN from early in development to adulthood (the expression pattern of these genes in the brain is restricted to the mdDA system). It has been shown that the En1 participates directly in the regulation of mdDA apoptosis, a proposed mechanism for Parkinson’s disease. Indeed, the deletion of the two En1 leads to the prenatal loss of DA neurons in the SN, via apoptosis. Furthermore, the (En1+/-;En2 -/-) mice adult phenotype resembles key pathological features of PD – progressive degeneration of dopaminergic neurons restricted to the SN of young adult mice, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This phenotype shares molecular similarities with the Aphakia mutant, the Pitx3 mouse mutant. This raises the question whether these two genes interact functionally in the molecular developmental program of the mdDA system as well as in its adult physiology.
The practical goals for the coming time are to find the transcriptional regulatory networks of these genes, focusing on their role in the survival of the SN mDA neurons. This will be followed by both analyses in vitro and in vivo of the genes found. The general aim, with a wider time scope, is to better understand mdDA development, maintenance and function, thereby enhancing the possibilities for clinical intervention in human mdDA pathology