Proposal of a model of mammalian neural induction

Abstract

How does the vertebrate embryo make a nervous system? This complex question has been at the center of developmental biology for many years. The earliest step in this process - the induction of neural tissue - is intimately linked to patterning of the entire early embryo, and the molecular and embryological of basis these processes are beginning to emerge. Here, we analyze classic and cutting-edge findings on neural induction in the mouse. We find that data from genetics, tissue explants, tissue grafting, and molecular marker expression support a coherent framework for mammalian neural induction. In this model, the gastrula organizer of the mouse embryo inhibits BMP signaling to allow neural tissue to form as a default fate-in the absence of instructive signals. The first neural tissue induced is anterior and subsequent neural tissue is posteriorized to form the midbrain, hindbrain, and spinal cord. The anterior visceral endoderm protects the pre-specified anterior neural fate from similar posteriorization, allowing formation of forebrain. This model is very similar to the default model of neural induction in the frog, thus bridging the evolutionary gap between amphibians and mammals.

Figure 1

Signaling centers and molecules implicated in neural induction. A 7.0 mid streak embryo is shown in gray. In the proximal extra-embryonic region (EE), BMP4 and BMP2 are expressed (dark green). These factors activate signaling through phosphorylation of Smad1 (light green) in the primitive streak and some extra-embryonic tissues. At the anterior end of the embryo, the anterior visceral endoderm (AVE, yellow) expresses Lefty and Cerberus (cer-l). In the embryonic region, the anterior and distal epiblast express early neural markers such as Otx2 (blue). At the posterior end of the embryo, the mesendoderm forms from the primitive streak (PS, orange), which expresses Fgfs, Wnts, and Nodal. At the anterior end of the primitive streak, the mid-gastrula organizer (maroon) expresses Chordin (chd), a BMP inhibitor.

Figure 2

Neural induction in the mouse embryo from embryonic day 6.0–8.5. The epiblast of the early mouse embryo (day 6.0–6.5) exists in a pre-neural state (light blue). At pre-streak stages, the only evidence of embryonic polarity is the anterior visceral endoderm (AVE, yellow) overlying the anterior epiblast. As gastrulation initiates, the early primitive streak (orange) forms in the posterior embryo, with the early gastrula organizer (GO, maroon) anterior to the streak. By mid-streak stages, the AVE has migrated proximally, the primitive streak has elongated distally, and early neural markers are expressed (blue) in the distal/anterior half of the embryo. These markers represent the specification of neural tissue. As gastrulation proceeds, anterior neural precursors (blue) migrate anteriorly, to become juxtaposed with the AVE. The node is located at the distal end of the embryo by late streak stages and anterior mesendoderm (AME, maroon) extends anteriorly from the node during late streak and allantoic bud stages. Determination of anterior neural tissue occurs during late streak stages and is complete by the late allantoic bud stage. By e8.5, neural induction is mostly completed and the neural plate begins to form a tube, through neurulation. The neural tissue is comprised of forebrain (FB, blue), midbrain (MB, light blue), hindbrain (HB, light blue), and spinal cord (SC, turquoise). The anterior mesendoderm underlies the neural tissue and is required for its maintenance. This image is not drawn to scale.