Retinoic acid (RA) signaling is required during the development of several organs, including the eyes, diaphragm, limbs and brain. Both loss and gain of RA signaling cause defects in these organs, indicating that precise regulation of the pathway is required for appropriate development. In target cells, RA binds to heterodimeric receptor complexes composed of a retinoic acid receptor (RAR) and a retinoid X receptor (RXR).
Patients with mutations in RARb display a progressive motor impairment that considerably affects their quality of life and can lead to death. Dystonia suggests that their motor impairment is caused, at least in part, by defects in striatal Medium Spiny Neurons (MSNs) in the striatum.
RARb appears to play two successive roles in the striatum; it first regulates the development of specific subpopulations of Striatonigral neurons and in post-natal life it might be required for the regulation of dopamine signaling and/or the survival of subpopulations of Striatopallidal neurons.
In this EU RARE-funded project RAinRARE, I will use human induced pluripotent stem cells (iPSCs) to gain better insights into the mechanisms of a rare, but lethal disease (MCOPS12) which is linked to the mutations in the retinoic acid receptor beta (RARb), and that shows progressive motor and cognitive impairments in children.