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First published online August 2, 2004
doi: 10.1242/10.1242/dev.01282

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Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial motoneuron progenitors by homeodomain proteins

Omar Abdel Samad^1,*, Marc J. Geisen^1,*, Giuliana Caronia², Isabelle Varlet^3,, Vincenzo Zappavigna^2,4, Johan Ericson⁵, Christo Goridis⁶ and Filippo M. Rijli^1,

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, BP 10142-67404 Illkirch Cedex, CU de Strasbourg, France
² DIBIT, H San Raffaele, Via Olgettina 58, 20132 Milano, Italy
³ Laboratoire de Génétique et Physiologie du Développement, IBDM, CNRS/INSERM/Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 9, France
⁴ Department of Animal Biology, University of Modena and Reggio Emilia, via Campi 213/D, 41100 Modena, Italy
⁵ Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden
⁶ CNRS UMR8542, Ecole Normale Supérieure, Département de Biologie, 75005 Paris, France

Author for correspondence (e-mail: rijli{at}igbmc.u-strasbg.fr)

Accepted 13 May 2004

Little is known about the molecular mechanisms that integrate anteroposterior (AP) and dorsoventral (DV) positional information in neural progenitors that specify distinct neuronal types within the vertebrate neural tube. We have previously shown that in ventral rhombomere (r)4 of Hoxb1 and Hoxb2 mutant mouse embryos, Phox2b expression is not properly maintained in the visceral motoneuron progenitor domain (pMNv), resulting in a switch to serotonergic fate. Here, we show that Phox2b is a direct target of Hoxb1 and Hoxb2. We found a highly conserved Phox2b proximal enhancer that mediates rhombomere-restricted expression and contains separate Pbx-Hox (PH) and Prep/Meis (P/M) binding sites. We further show that both the PH and P/M sites are essential for Hox-Pbx-Prep ternary complex formation and regulation of the Phox2b enhancer activity in ventral r4. Moreover, the DV factor Nkx2.2 enhances Hox-mediated transactivation via a derepression mechanism. Finally, we show that induction of ectopic Phox2b-expressing visceral motoneurons in the chick hindbrain requires the combined activities of Hox and Nkx2 homeodomain proteins. This study takes an important first step to understand how activators and repressors, induced along the AP and DV axes in response to signaling pathways, interact to regulate specific target gene promoters, leading to neuronal fate specification in the appropriate developmental context.

Key words: Hoxb1, Hoxb2, Nkx2.2, Pbx1a, Prep1, Motoneuron, Hindbrain, Transcriptional activation, Derepression, Ternary complex, PH and P/M binding sites, AP and DV integration

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