Department of Life Sciences and Medicine (DLSM), University of Luxembourg, L-4362, Belvaux, Luxembourg.
Published: January 2024
AI Article Synopsis
Article Abstract
Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.
Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation.
Parkinson disease (PD) is caused by the loss of ventral midbrain dopaminergic neurons (mDANs) in the substantia nigra pars compacta (SNpc). These cells are especially vulnerable to stress but can be protected by autophagy enhancement strategies in vitro and in vivo. In our recent study, we focused on the LIM (Lin11, Isl-1, and Mec-3)-domain homeobox transcription factors LMX1A (LIM homeobox transcription factor 1 alpha) and LMX1B (LIM homeobox transcription factor 1 beta), crucial drivers of mDAN differentiation with roles in autophagy gene expression for stress protection in the developed brain.
The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors that provide cellular stress protection. Their suppression dampens the autophagy response, lowers mitochondrial respiration, and elevates mitochondrial ROS, and their inducible overexpression protects against rotenone toxicity in human iPSC-derived mDANs in vitro.
Combining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic neuron (mDAN) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control, and genetically unrelated iPSCs into mDANs. Using automated fluorescence microscopy in 384-well-plate format, we identified elevated levels of α-synuclein (αSyn) and serine 129 phosphorylation, reduced dendritic complexity, and mitochondrial dysfunction.
Brain stroke lesion segmentation is of great importance for stroke rehabilitation neuroimaging analysis. Due to the large variance of stroke lesion shapes and similarities of tissue intensity distribution, it remains a challenging task. To help detect abnormalities, the anatomical symmetries of brain magnetic resonance (MR) images have been widely used as visual cues for clinical practices.
