QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online September 26, 2008
doi: 10.1242/10.1242/dev.027003

This Article Figures Only Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Omodei, D. Articles by Simeone, A. Search for Related Content PubMed PubMed Citation Articles by Omodei, D. Articles by Simeone, A. Social Bookmarking                         What's this?

Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon

Daniela Omodei^1,*, Dario Acampora^1,2,*, Pietro Mancuso¹, Nilima Prakash³, Luca Giovanni Di Giovannantonio¹, Wolfgang Wurst^3, and Antonio Simeone^1,2,

¹ CEINGE Biotecnologie Avanzate, via Comunale Margherita 482, 80145 Naples, Italy and SEMM European School of Molecular Medicine - Naples site, Italy.
² Institute of Genetics and Biophysics `A. Buzzati-Traverso', CNR, Via P. Castellino 111, 80131 Naples, Italy.
³ Max-Planck-Insitute of Psychiatry, Molecular, Neurogenetics, Kraepelinstr. 2-16, 80804 Munich, Germany and Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

Authors for correspondence (e-mails: simeone{at}ceinge.unina.it; wurst{at}helmholtz-muenchen.de)

Accepted 2 September 2008

Meso-diencephalic dopaminergic (mdDA) neurons control voluntary movement, cognition and the reward response, and their degeneration is associated with Parkinson's disease (PD). Prospective cell transplantation therapies for PD require full knowledge of the developmental pathways that control mdDA neurogenesis. We have previously shown that Otx2 is required for the establishment of the mesencephalic field and molecular code of the entire ventral mesencephalon (VM). Here, we investigate whether Otx2 is a specific determinant of mesencephalic dopaminergic (mesDA) neurogenesis by studying mouse mutants that conditionally overexpress or lack Otx2. Our data show that Otx2 overexpression in the VM causes a dose-dependent and selective increase in both mesDA progenitors and neurons, which correlates with a remarkable and specific enhancement in the proliferating activity of mesDA progenitors. Consistently, lack of Otx2 in the VM specifically affects the proliferation of Sox2⁺ mesDA progenitors and causes their premature post-mitotic transition. Analysis of the developmental pathway that controls the differentiation of mesDA neurons shows that, in the absence of Otx2, the expression of Lmx1a and Msx1, and the proneural genes Ngn2 and Mash1 is not activated in Sox2⁺ mesDA progenitors, which largely fail to differentiate into Nurr1⁺ mesDA precursors. Furthermore, proliferation and differentiation abnormalities exhibit increasing severity along the anterior-posterior (AP) axis of the VM. These findings demonstrate that Otx2, through an AP graded effect, is intrinsically required to control proliferation and differentiation of mesDA progenitors. Thus, our data provide new insights into the mechanism of mesDA neuron specification and suggest Otx2 as a potential target for cell replacement-based therapeutic approaches in PD.

Key words: Dopaminergic neuron, Cell proliferation, Cell differentiation, Otx2, Wnt1, Sox2, Lmx1a, Msx1, Ngn2, Parkinson's disease

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Related articles in Development:

Dopaminergic neurogenesis expands with Otx2

Development 2008 135: e2005. [Full Text]  

This article has been cited by other articles:

				N. Prakash, E. Puelles, K. Freude, D. Trumbach, D. Omodei, M. Di Salvio, L. Sussel, J. Ericson, M. Sander, A. Simeone, et al. Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain Development, August 1, 2009; 136(15): 2545 - 2555. [Abstract] [Full Text] [PDF]

				M. Tang, Y. Miyamoto, and E. J. Huang Multiple roles of {beta}-catenin in controlling the neurogenic niche for midbrain dopamine neurons Development, June 15, 2009; 136(12): 2027 - 2038. [Abstract] [Full Text] [PDF]

				W.S. Layman, D.P. McEwen, L.A. Beyer, S.R. Lalani, S.D. Fernbach, E. Oh, A. Swaroop, C.C. Hegg, Y. Raphael, J.R. Martens, et al. Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome Hum. Mol. Genet., June 1, 2009; 18(11): 1909 - 1923. [Abstract] [Full Text] [PDF]

				D. Omodei, D. Acampora, P. Mancuso, N. Prakash, L. G. Di Giovannantonio, W. Wurst, and A. Simeone Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon J. Cell Sci., October 15, 2008; 121(20): e1 - e1. [Full Text]