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- Generating asymmetries in the early vertebrate embryo: the role of the Cerberus-like familyPublication . Belo, José A.; Silva, Ana C.; Borges, Ana; Filipe, Mário; Bento, Margaret; Gonçalves, Lisa; Vitorino, Marta; Salgueiro, Ana Marisa; Texeira, Vera; Tavares, Ana T.; Marques, SaraOne fundamental aspect of vertebrate embryonic development is the formation of the body plan. For this process, asymmetries have to be generated during early stages of development along the three main body axes: Anterior-Posterior, Dorso-Ventral and Left-Right. We have been studying the role of a novel class of molecules,the Cerberus/Dan gene family. These are dedicated secreted antagonists of three major signaling pathways: Nodal, BMP and Wnt. Our studies contribute to the current view that the fine tuning of signaling is controlled by a set of inhibitory molecules rather than by activators. In this context, the Cerberus-like molecules emerge as key players in the regulation and generation of asymmetries in the early vertebrate embryo.
- The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axisPublication . Marques, Sara; Borges, Ana; Silva, Ana Cristina; Freitas, Sandra; Cordenonsi, M.; Belo, José A.Correct establishment of the left/right (L/R) body asymmetry in the mouse embryo requires asymmetric activation of the evolutionarily conserved Nodal signaling cascade in the left lateral plate mesoderm (L-LPM). Furthermore, the presence of Nodal in the node is essential for its own expression in the L-LPM. Here, we have characterized the function of cerl-2, a novel Nodal antagonist, which displays a unique asymmetric expression on the right side of the mouse node. cerl-2 knockout mice display multiple laterality defects including randomization of the L/R axis. These defects can be partially rescued by removing one nodal allele. Our results demonstrate that Cerl-2 plays a key role in restricting the Nodal signaling pathway toward the left side of the mouse embryo by preventing its activity in the right side.
- Study of genetic and biochemical interactions with mouse Cerberus-like genesPublication . Borges, Ana Cristina Ribeiro; Jacinto, A.; Vicente, A.O organismo dos vertebrados está organizado ao longo de 3 eixos principais, antero-posterior (A-P), dorso-ventral (D-V) e direito-esquerdo (D-E). que são especificados durante estádios precoces da vida embrionária. A base genética e molecular necessária para estabelecer os eixos principais tem sido descrita e as moléculas da superfamília "transforming growth factor-p" (TGF-P), como por exemplo, proteínas morfogenéticas do osso (BMPs) e Nodal, desempenham funções essenciais na padronização do embrião. A regulação da actividade destas moléculas é fundamental, de modo produzir a resposta biológica adequada. Cerberus-like (Cer-1) é um membro da família Cerberus/Dan, e da superfamília TGF-p, e um inibidor potente de BMPs e Nodal. Cer-1 é expresso em estádios precoces do desenvolvimento embrionário de ratinho. Este gene foi inactivado por mutagénese dirigida em células estaminais embrionárias, mas não possibilitou uma caracterização funcional, uma vez que os mutantes se apresentam viáveis e sem fenótipo. Na tentativa de determinar a função biológica de Cer-l, foram gerados vários duplos mutantes. A partir destes estudos foi possível concluir que Cer-1 não é epistático com Noggin. outro inibidor de BMPs, nem com o factor de transcrição Goosecoid. O estudo da dupla mutação de Cer-l e de Cripto, um co-receptor de Nodal, permitiu reconhecer a importância de Cer-1 como importante regulador da actividade de Nodal. Esta análise revelou a existência de uma via de sinalização de Nodal, independente de Cripto, que pode ser inibida por Cer-1 e está envolvida na especificação dos eixos A-P e D-V.
- Cripto-independent Nodal signaling promotes positioning of the A-P axis in the early mouse embryoPublication . Liguori, Giovanna; Borges, Ana; D'Andrea, Daniela; Liguoro, Annamaria; Gonçalves Dias da Silva, Lisa; Salizueiro, Ana Marisa; Persico, M. Graziella; Belo, José A.During early mouse development, the TGF beta-related protein Nodal specifies the organizing centers that control the formation of the anterior-posterior (A-P) axis. EGF-CFC proteins are important components of the Nodal signaling pathway, most likely by acting as Nodal coreceptors. However, the extent to which Nodal activity depends on EGF-CFC proteins is still debated. Cripto is the earliest EGF-CFC gene expressed during mouse embryogenesis and is involved in both A-P axis orientation and mesoderm formation. To investigate the relation between Cripto and Nodal in the early mouse embryo, we removed the Nodal antagonist Cerberus 1 (Cer1) and simultaneously Cripto, by generating Cer1;Cripto double mouse mutants. We observed that two thirds of the Cer1,Cripto double mutants are rescued in processes that are severely compromised in Cripto(-/-) embryos, namely A-P axis orientation, anterior mesendoderm and posterior neuroectoderin formation. The observed rescue is strongly reduced in Cer1;Cripto;Nodal triple mutants, suggesting that Nodal can signal extensively in the absence of Cripto, if Cer1 is also inhibited. This signaling activity drives A-P axis positioning. Our results provide evidence for the existence. of Cripto-independent signaling mechanisms, by which Nodal controls axis specification in the early mouse embryo. (C) 2007 Elsevier Inc. All rights reserved.