While LMX1A labels all the cells in the mDA lineage, from proliferating progenitors to postmitotic neuroblasts and mDAn (Andersson et al, 2006), NURR1 labels all postmitotic cells, from mDA neuroblasts to neurons. Both Nurr1 and Pitx3 are required for mDA neuron differentiation and survival (Zetterstrom et al, 1997 Nunes et al, 2003 Smidt et al, 2004 Maxwell et al, 2005). Notably, LMX1A forms an autoregulatory loop together with LMX1B and WNT1, and directly regulates the expression of the orphan nuclear receptor Nurr1/Nr4a2 and the paired-like homeodomain transcription factor 3 ( Pitx3) gene (Chung et al, 2009). A second main pathway involves WNT1, which regulates and is regulated by LMX1A, a LIM homeodomain transcription factor required for mDAn specification (Andersson et al, 2006). One such pathway is that formed by SHH, which regulates and is regulated by FOXA2, a forkhead/winged helix transcription factor required for mDAn development (Ferri et al, 2007). The development of mDAn is controlled by a combination of cell extrinsic and intrinsic signals (Prakash & Wurst, 2006 Ribes et al, 2010 Arenas et al, 2015). Moreover, the mechanism of action and molecular targets of PBX transcription factors in mDAn, as well as any role in neurodegenerative diseases, such as PD, remains unknown. Thus, the function and precise role of different PBX family members on mDAn remains largely unexplored. However, to date only a very mild mDAn axon guidance phenotype has been described in Pbx1 null embryos (Sgado et al, 2012). Expression of Pbx genes has been detected in both the mouse and human midbrain as well as mDAn (Thompson et al, 2006 Yin et al, 2009 Ganat et al, 2012 Sgado et al, 2012 Veenvliet et al, 2013). The PBX family of transcription factors is composed of four members in mammals (PBX1-4) (Moens & Selleri, 2006 Longobardi et al, 2013). Current treatments for PD are symptomatic and there is a need for therapies capable of changing the course of this disease. The progressive degeneration of substantia nigra (SN) mDAn gives rise to some of the main motor features of PD (Lees et al, 2009). Midbrain dopaminergic neurons (mDAn) play a central role in the modulation of several brain functions, including voluntary movements, emotion, and cognition. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.
Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. 9 Present address: Department of Chemistry, Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, UK.8 Present address: Genetics Department, Stanford University, Stanford, CA, USA.7 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
6 Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.5 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.4 Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.3 Psychiatric Stem Cell Group, Neurogenetics Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.2 Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.1 Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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