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

Rémy Liechti,Morten Meyer,Hans Rudolf Widmer,Charlotte H Jensen,Stefano Di Santo,Stefanie Seiler,Angélique D Ducray,Pia Jensen,Tim Douglas Aumann

doi:10.1371/journal.pone.0116088

Rémy Liechti, Morten Meyer + Show 7 more

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https://doi.org/10.1371/journal.pone.0116088

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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.

Highlights

Idiopathic Parkinson’s disease (PD) is a chronic and slowly progressive disorder of the central nervous system, clinically defined by any combination of the cardinal motor symptoms tremor at rest, bradykinesia and muscle rigidity
The dopaminergic neurons of the substantia nigra pars compacta (SNc) mainly project to the dorsal striatum, forming the mesostriatal system, which is affected in PD
The highest density of FA1/dlk1-ir cells was found in the substantia nigra (SN), the ventral tegmental area (VTA), the deep mesencephalic nucleus (DpMe) and the periaqueductal gray (PAG) (Fig. 1)

Summary

Introduction

Idiopathic Parkinson’s disease (PD) is a chronic and slowly progressive disorder of the central nervous system, clinically defined by any combination of the cardinal motor symptoms tremor at rest, bradykinesia and muscle rigidity. The motor symptoms result mainly from the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) [1]. Some studies have revealed different vulnerabilities for subpopulations of dopaminergic neurons in the SNc [3,4,5]. The dopaminergic neurons of the SNc mainly project to the dorsal striatum, forming the mesostriatal system, which is affected in PD. In turn the ventral tegmental area (VTA) consists of dopaminergic neurons projecting to the ventral striatum and pallidum, prefrontal cortex, amygdala, and hippocampus. This mesocorticolimbic system plays a key role in the motivational aspects of drug addiction as well as in emotional behavior [6,7,8]

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