Molecular mechanisms controlling brain development: an overview of neuroepithelial secondary organizers CLAUDIA VIEIRA, ANA POMBERO, RAQUEL GARCÍA–LOPEZ, LOURDES GIMENO, DIEGO ECHEVARRIA and SALVADOR MARTÍNEZ* Alicante Neuroscience Institute, Miguel Hernandez University, CSIC, San Juan de Alicante, Alicante, Spain ABSTRACT The vertebrate Central Nervous System (CNS) originates from the embryonic dorsal ectoderm. Differentiation of the neural epithelium from the ectoderm and the formation of the neural plate constitute the first phase of a complex process called neurulation which culminates in the formation of the neural tube, the anlage of the CNS in sauropsids and mammals (for review see Smith and Schoenwolf, 1997; Colas and Schoenwolf, 2001). At neural plate and neural tube stages, local signaling centers in the neuroepithelium, known as secondary organizers, refine the antero-posterior specification of different neural territories (for review see Echevarria et al., 2003; Stern et al., 2006; Woltering and Durston, 2008). In this review, we will describe the principle aspects of CNS development in birds and mammals, starting from early stages of embryogenesis (gastrulation and neurulation) and culminating with the formation of a variety of different regions which contribute to the structural complexity of the brain (regionalization and morphogenesis). We will pay special attention to the cellular and molecular mechanisms involved in neural tube regionalization and the key role played by localized secondary organizers in the patterning of neural primordia. KEY WORDS: patterning, neural plate, neural tube, gastrulation, neurulation, secondary organizer, anterior neural ridge, zona limitans intrathalamica, isthmic organizer Neural plate and neural tube formation A fundamental early step in neural development is the allocation of a group of ectodermal cells as precursors of the entire nervous system (Hemmati-Brivanlou and Melton, 1997). This process involves an inductive interaction first demon- strated in amphibian embryos by Spemann and Mangold in the 1920’s (see Spemann and Mangold, 2001). Their experiments which involved the grafting of differently pigmented species of newt established the concept of neural induction as an instruc- tive interaction between the dorsal lip of the blastopore (the “organizer”) and the neighboring ectoderm. The discovery of a neural organization center for the amphibian gastrula initiated a search for homologous structures in other vertebrates. Soon thereafter, the equivalent region was discovered in most verte- brate species, including the shield of teleosts. In birds and mammals, the region was named “Hensen’s node” and “the node”, respectively. When C.H. Waddington transplanted the Hensen node of a chick embryo, he observed the induction of Int. J. Dev. Biol. 54: 7-20 (2010) doi: 10.1387/ijdb.092853cv THE INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY www.intjdevbiol.com *Address correspondence to: Salvador Martinez. Institute of Neuroscience Alicante. Miguel Hernandez University (CSIC), Ctra. de Valencia Km 18, E-03550 San Juan de Alicante, Alicante, Spain. Fax. +34-965-919-555. e-mail: smartinez@umh.es Tel:+34-965-919-556. Web: http://www.ina.umh.es/grupos-detalle.aspx?grupo=6 Accepted: 13 March 2009. Final author-corrected PDF published online: 25 September 2009. ISSN: Online 1696-3547, Print 0214-6282 © 2009 UBC Press Printed in Spain Abbreviations used in this paper: ANR, anterior neural ridge; AP, antero- posterior; BMP, bone morphogenetic protein; DV, dorso-ventral; FGF, fibroblast growth factor; IsO, Isthmic organizer; ML, medio-lateral; TGF, transforming growth factor; ZLI, zona limitans intrathalamica. an ectopic neural plate or the formation of a partial new embryonic axis containing neural tube, notochord and somites (Waddington, 1933; Waddington, 1936). This demonstration provided the first evidence that in chick embryos, the nervous system is induced by signals from non-neural cells. Recent works demonstrated that the capacity of ectodermal cells to undergo neural differentiation represents their default state. In fact, neural differentiation must be suppressed in the lateral ectoderm by signals transmitted between neighboring cells, in order to develop as epidermis. These molecular signals are members of the bone morphogenetic protein (BMP) subclass of transforming growth factor β (TGF-β)-related proteins (for re- view see Wittler and Kessel, 2004).