title: Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency.
abstract: Selective neuronal loss in the substantia nigra (SNc), as described for Parkinson's disease (PD) in humans and for Pitx3 deficiency in mice, highlights the existence of neuronal subpopulations. As yet unknown subset-specific gene cascades might underlie the observed differences in neuronal vulnerability. We identified a developmental cascade in mice in which Ahd2 (Aldh1a1) is under the transcriptional control of Pitx3. Interestingly, Ahd2 distribution is restricted to a subpopulation of the meso-diencephalic dopaminergic (mdDA) neurons that is affected by Pitx3 deficiency. Ahd2 is involved in the synthesis of retinoic acid (RA), which has a crucial role in neuronal patterning, differentiation and survival in the brain. Most intriguingly, restoring RA signaling in the embryonic mdDA area counteracts the developmental defects caused by Pitx3 deficiency. The number of tyrosine hydroxylase-positive (TH+) neurons was significantly increased after RA treatment in the rostral mdDA region of Pitx3-/- embryos. This effect was specific for the rostral part of the developing mdDA area, and was observed exclusively in Pitx3-/- embryos. The effect of RA treatment during the critical phase was preserved until later in development, and our data suggest that RA is required for the establishment of proper mdDA neuronal identity. This positions Pitx3 centrally in a mdDA developmental cascade linked to RA signaling. Here, we propose a novel mechanism in which RA is involved in mdDA neuronal development and maintenance, providing new insights into subset-specific vulnerability in PD.
authors.affiliation: Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Frank M J
authors.initials: FM
authors.lastname: Jacobs
authors.forename: Simone M
authors.initials: SM
authors.lastname: Smits
authors.forename: Cornelle W
authors.initials: CW
authors.lastname: Noorlander
authors.forename: Lars
authors.initials: L
authors.lastname: von Oerthel
authors.forename: Annemarie J A
authors.initials: AJ
authors.lastname: van der Linden
authors.forename: J Peter H
authors.initials: JP
authors.lastname: Burbach
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000080924:Aldehyde Dehydrogenase 1 Family; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D004027:Diencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D050697:Retinal Dehydrogenase; D015398:Signal Transduction; D013378:Substantia Nigra / Q000196:embryology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D004298:Dopamine