Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.
Selective degeneration of midbrain dopaminergic (mDA) neurons is associated with Parkinson's disease (PD), and thus an in-depth understanding of molecular pathways underlying mDA development will be crucial for optimal bioassays and cell replacement therapy for PD. In this study, we identified a novel Wnt1-Lmx1a autoregulatory loop during mDA differentiation of ESCs and confirmed its in vivo presence during embryonic development. We found that the Wnt1-Lmx1a autoregulatory loop directly regulates Otx2 through the beta-catenin complex and Nurr1 and Pitx3 through Lmx1a. We also found that Lmx1a and Lmx1b cooperatively regulate mDA differentiation with overlapping and cross-regulatory functions. Furthermore, coactivation of both Wnt1 and SHH pathways by exogenous expression of Lmx1a, Otx2, and FoxA2 synergistically enhanced the differentiation of ESCs to mDA neurons. Together with previous works, this study shows that two regulatory loops (Wnt1-Lmx1a and SHH-FoxA2) critically link extrinsic signals to cell-intrinsic factors and cooperatively regulate mDA neuron development.
Chung
Sangmi
S
Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
Leung
Amanda
A
Han
Baek-Soo
BS
Chang
Mi-Yoon
MY
Moon
Jung-Il
JI
Kim
Chun-Hyung
CH
Hong
Sunghoi
S
Pruszak
Jan
J
Isacson
Ole
O
Kim
Kwang-Soo
KS
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D060850:LIM-Homeodomain Proteins; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism*
C496503:Foxa2 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C465570:Shh protein, mouse; D014157:Transcription Factors; D051155:Wnt1 Protein; C433629:homeobox protein PITX3; D051542:Hepatocyte Nuclear Factor 3-beta; D004298:Dopamine