Dickkopf 3 promotes the differentiation of a rostrolateral midbrain dopaminergic neuronal subset in vivo and from pluripotent stem cells in vitro in the mouse

Yoshiyasu Fukusumi, Florian Meier, Sebastian Götz, Friederike Matheus, Martin Irmler, Ruth Beckervordersandforth, Theresa Faus-Kessler, Eleonora Minina, Benedict Rauser, Jingzhong Zhang, Ernest Arenas, Elisabet Andersson, Christof Niehrs, Johannes Beckers, Antonio Simeone, Wolfgang Wurst, Nilima Prakash

Research output: Contribution to journalArticlepeer-review

Abstract

Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson’s disease (PD). However, the precise functions of WNT1/β-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/β-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1α) and PITX3 (paired-like homeodomain transcription factor 3) expression in the correspondingmdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD.

Original languageEnglish
Pages (from-to)13385-13401
Number of pages17
JournalJournal of Neuroscience
Volume35
Issue number39
DOIs
Publication statusPublished - Sep 30 2015

Keywords

  • Differentiation
  • DKK3
  • Mouse
  • Stem cell
  • Substantia nigra dopamine neuron
  • WNT1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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