title: Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway.
abstract: 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.
authors: Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors: Sangmi
authors: S
authors: Chung
authors: Amanda
authors: A
authors: Leung
authors: Baek-Soo
authors: BS
authors: Han
authors: Mi-Yoon
authors: MY
authors: Chang
authors: Jung-Il
authors: JI
authors: Moon
authors: Chun-Hyung
authors: CH
authors: Kim
authors: Sunghoi
authors: S
authors: Hong
authors: Jan
authors: J
authors: Pruszak
authors: Ole
authors: O
authors: Isacson
authors: Kwang-Soo
authors: KS
authors: Kim
mesh_terms: 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*
chemical_list: 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