Characterization of fetal antigen 1/delta-like 1 homologue expressing cells in the rat nigrostriatal system: effects of a unilateral 6-hydroxydopamine lesion

PLoS One. 2015 Feb 27;10(2):e0116088. doi: 10.1371/journal.pone.0116088. eCollection 2015.

Abstract

Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Female
  • Gene Expression*
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mesencephalon / metabolism
  • Mesencephalon / pathology
  • Neurons / metabolism
  • Oxidopamine / adverse effects
  • Phenotype
  • Protein Binding
  • Protein Transport
  • Rats
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Biomarkers
  • Dlk1 protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oxidopamine
  • Tyrosine 3-Monooxygenase

Grants and funding

This research was supported by the Swiss Parkinson Foundation, the HANELA Foundation and the Swiss National Science Foundation (No. 3100A0-112529 and 31003A_135565). Pia Jensen and Morten Meyer were supported by the Danish Parkinson Association, IMK Almene Fond, Kirsten and Freddy Johansens Fond and Hørslev Fonden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.