Wnt1-lmx1a Forms a Novel Autoregulatory Loop and Controls Midbrain Dopaminergic Differentiation Synergistically with the SHH-FoxA2 Pathway

Sangmi Chung, Amanda Leung, Baek Soo Han, Mi Yoon Chang, Jung Il Moon, Chun Hyung Kim, Sunghoi Hong, Jan Pruszak, Ole Isacson, Kwang Soo Kim

Research output: Contribution to journalArticle

126 Citations (Scopus)

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 β-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.

Original languageEnglish
Pages (from-to)646-658
Number of pages13
JournalCell Stem Cell
Volume5
Issue number6
DOIs
Publication statusPublished - 2009 Dec 4

Keywords

  • HUMDISEASE
  • STEMCELL

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Chung, S., Leung, A., Han, B. S., Chang, M. Y., Moon, J. I., Kim, C. H., Hong, S., Pruszak, J., Isacson, O., & Kim, K. S. (2009). Wnt1-lmx1a Forms a Novel Autoregulatory Loop and Controls Midbrain Dopaminergic Differentiation Synergistically with the SHH-FoxA2 Pathway. Cell Stem Cell, 5(6), 646-658. https://doi.org/10.1016/j.stem.2009.09.015