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

Abstract

Fetal antigen 1/deltalike 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a noncanonical 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/dlk1immunoreactive (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/dlk1ir 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. Colocalization and tracing studies demonstrated that FA1/dlk1ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6OHDA lesions resulted in loss of both FA1/dlk1ir and THir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1ir cells (by 70%) were detected in dopaminedepleted striata as compared to unlesioned controls. The higher number of FA1/dlk1ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was upregulated in intrinsic cells in response to the 6OHDAmediated loss of FA1/dlk1expressing 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 dopaminedepleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.