The Sokol Laboratory

Mechanisms of early neural development

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 The central nervous system forms in vertebrate embryos as a result of inductive interactions between competent ectoderm and a special dorsal signaling center, known in amphibians as the Spemann organizer. Organizer cells, corresponding to dorsal mesoderm, secrete a large number of factors, which can activate neural tissue specific genes in responding ectoderm. Complex interactions between the products encoded by these genes result in the differentiation of neurons and glial cells, organized in a specific mediolateral and anteroposterior pattern. Several signaling pathways, triggered by bone morphogenetic proteins (BMP), fibroblast growth factors (FGF) and Wnt proteins were implicated in early neural development in vertebrates, however, underlying molecular mechanisms are not understood in sufficient detail.

Our studies show that Frodo, a new signaling protein, plays an important role in the specification of the neural tissue. Frodo is a founding member of a family of related proteins that may operate in multiple signaling pathways (reviewed by Brott and Sokol, 2005). Using antisense morpholino oligonucleotides (MO), an efficient in vivo method of inactivating a gene product, we have demonstrated an essential role for Frodo in neural development (Hikasa and Sokol, 2004). Depletion of Frodo in presumptive mesoderm resulted in a selective defect in early organizer genes, such as Chordin, Xenopus nodal-related 3 and Cerberus , while other tested genes, such as Goosecoid and Siamois remained unchanged. Since both Siamois and Xnr3 are direct targets of Wnt signaling, this result is quite unexpected and suggests a role for Frodo in other signaling pathways besides the Wnt pathway. The involvement of Frodo in organizer formation and organizer-specific gene expression is supported by deficient head development in Frodo-depleted embryos (Hikasa and Sokol, 2004).

Moreover, targeted depletion of Frodo in neuroectoderm prevented activation of the neural markers Sox2 and Nrp1 at both neural plate and neural tube stages (Hikasa and Sokol, 2004) (Fig. 1). This effect on Sox2 activation has been observed as early as the gene is detectable at the beginning of gastrulation, suggesting that Frodo functions at the earliest stages of neural induction. This result establishes a requirement for a signaling protein in the activation of an early pan-neural marker in vertebrates.

Fig. 1. Frodo is required for Sox2 expression. In situ hybridization shows that the pan-neural marker Sox2 is downregulated in neural plate cells depleted of Frodo with an antisense morpholino (B, right side). A, control morpholino.

We found that Frodo associates with TCF and a novel kinase, which are both involved in early patterning events. Our current experiments are aimed to characterize new molecular pathways that involve Frodo and operate to regulate transcription of genes involved in neurogenesis and gliogenesis.

We are also studying Frodo homologues in other vertebrates, such as mouse (Fig. 2, left) and zebrafish (right), and have shown that they have a conserved pattern of expression in tissues undergoing morphogenetic changes, such as epithelial-mesenchymal transition.

Fig. 2. Frodo homologues are expressed in similar pattern in the mouse (left) and zebrafish (right) embryos.