Новые функции белков семейства Noggin: ингибирование сигнальных каскадов Activin/Nodal и Wnt в эмбриональном развитии

Одной из важнейших задач современной биологии развития является поиск и изучение факторов, обеспечивающих индукционные взаимодействия клеток и тканей в ходе эмбриогенеза. Секретируемый белок Noggin (Nogginl) является первым идентифицированным белковым фактором, участвующим в первичной эмбриональной индукции. Он был открыт Ричардом Харландом в 1992 г. у шпорцевой лягушки Xenopus как нейральный индуктор, продуцируемый шпемановским организатором. Nogginl способен связывать белки одной из субгрупп цитокинов TGF-(3, а именно Bone Morphogenetic Proteins (BMP) (Smith and Harland, 1992). Действуя вне клетки, BMP индуцирует ассоциацию специфических рецепторных серин-треониновых киназ I и II типа, что приводит к внутриклеточному фосфорилированию цитоплазматических белков Smadl/5/8, которые в паре со Smad4 мигрируют в ядро и регулируют ранскрипцию специфических генов-мишеней (Shi and Massague, 2003). Так как Noggin препятствует связыванию BMP с рецепторами (Groppe et al., 2002), это приводит к ингибированию сигнального пути, опосредованного Smadl/5/8. Благодаря этой функции, Nogginl, будучи эктопически экспрессирован в вентральной части эмбриона Xenopus, способен индуцировать вторичные оси, лишенные голов. В нормальном развитии Nogginl играет ключевую роль в различных процессах, включая индукцию нервной ткани и скелетной мускулатуры в раннем эмбриогенезе (Smith and Harland, 1992), развитие хрящей (Botchkarev et al., 1999) и дифференцировку волосяных фолликулов (Brunei et al., 1998; Botchkarev et al., 1999; Shi and Massague, 2003). Во многих экспериментальных системах, например, при изучении стволовых или раковых клеток, Nogginl используется в качестве искусственного ингибитора BMP-каскада. Считается общепризнанным, что Nogginl не является антагонистом для другой субгруппы лигандов TGF-J3, Activin/Nodal/TGFbeta, которые связываются с другими серин-треонин киназными рецепторами и регулируют транскрипцию другого набора генов-мишеней через внутриклеточный белок-посредник Smad2/3 (Branford and Yost, 2002). Известно, что ингибирование этого сигнального пути необходимо для правильной разметки мезодермы при гаструляции (Piccolo et al., 1999), развития переднего мозга (Meno et al., 2001) и установления право-левой ассимметрии (Grande and Patel, 2009).

Помимо «классического» Noggin 1, у позвоночных были найдены две других группы белков семейства Noggin, Noggin2 и Noggin4 (Furthauer et al., 1999; Fletcher et al., 2004; Eroshkin et al., 2006). Биологическая функция была показана в экспериментах только для Noggin2, который экспрессируется специфически в зачатке конечного мозга эмбрионов Xenopus и Danio. На основании этих данных было предположено, что Noggin2 может, по большей части, дублировать ВМР-антагонистическую функцию Nogginl (Furthauer et al., 1999). Однако, по нашему предположению, значительные различия в первичной структуре белков Noggin, которые принадлежат к разным белковым подсемействам (Eroshkin et al., 2006), и различающиеся паттерны их экспрессии указывают на возможные различия в репертуаре связываемых ими белков и предполагают различную биологическую функцию.

В связи с этим, задача настоящей работы — изучение механизмов функционирования данных белков и их роли в ранней тканевой дифференцировке — представляется весьма актуальной, как с точки зрения получения новых фундаментальных знаний, так и ввиду необходимости создания новых генно-инженерных продуктов для специфичного управления процессами жизнедеятельности и дифференцировки клеток.

Особенностью данной работы является использование в качестве основной экспериментальной модели эмбрионов шпорцевой лягушки Xenopus. Данная модель признается одной из наиболее перспективных для изучения механизмов реализации генетической информации в раннем эмбриогенезе и, кроме этого, представляет собой удобную тест-систему, позволяющую исследовать процессы in vivo.

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