Robert C. Angerer, Ph.D., Acting Chief
Research in the Developmental Mechanisms Section deals with a fundamental problem in animal development – how signaling interactions control regulatory state transitions during embryogenesis. Our work emphasizes that signals not only activate new gene regulatory networks, but also eliminate or alter pre-existing ones. This work is relevant to the mission of NIDCR in which a number of labs are studying how stem cells can be programmed for tissue repair and what regulates oncogenic transformation.
Our lab focuses on understanding how early embryonic territories are created as a result of signals that alter the regulatory states of cells – in particular, how they lead to the separation of fates of neuroectoderm from epidermal ectoderm and of endoderm from mesoderm. Because echinoderms and vertebrates share a common ancestor, and because fundamental regulatory mechanisms in the first steps of fate specification of similar tissues are often conserved, our studies can identify core regulatory processes that pattern vertebrate embryos. For example, we identified a large cohort of regulatory proteins expressed in the anterior region of the embryo, some of which have orthologs expressed in vertebrate forebrain development. Secondly, a low Wnt signaling environment is required for the expression of these genes in both sea urchin and vertebrate embryos. In addition, we have uncovered a Notch signaling-dependent regulatory device that separates endoderm from mesoderm, which may help explain why perturbations of Notch signaling affect the endoderm/mesoderm balance in several vertebrate model systems. Highlights of work over the past several years include a number of unexpected discoveries:
- Specification of different ectoderm cell types along the primary, anterior-posterior axis of the embryo relies not only on Wnt/beta-catenin, as previously shown, but also on Wnt/PCP and probably Wnt/Ca+2 signaling. We uncovered unexpected interactions among these Wnt signaling branches that together suppress anterior neuroectoderm fate in all but the anterior-most ectoderm, which is protected by Wnt antagonists.
- Wnt signaling through Wnt1 is required to maintain the body plan of the embryo by suppressing Nodal signaling, well after fates of most cells are specified. This late negative regulation is critical because Wnt/beta-catenin and Nodal are the cardinal signaling pathways that initially activate cell fate specification along the anterior-posterior and dorsal-ventral axes of the early embryo.
- Pharyngeal neurons are not of ectodermal origin, unexpectedly, but instead differentiate de novo from cells in the foregut endoderm of the fully formed gut, which has previously expressed the endoderm gene regulatory program. This finding challenges the dogma that nerves develop only from ectoderm. Using loss-of-function analyses, we established a regulatory path from Six3 through Nkx3-2 to SynaptotagminB that supports neural differentiation in foregut cells.
- Notch signaling specifically in mesoderm cells separates endoderm and mesoderm in the Wnt/beta-catenin-dependent endomesoderm field not only by activating the mesoderm gene regulatory network, but also by sequentially suppressing the endoderm network in two ways. It initially inhibits operation of an early endoderm regulatory circuit in the mesoderm by suppressing expression of a critical upstream transcription factor in this circuit. This circuit, which remains active in the endoderm, in turn, generates production of a Wnt ligand that reinforces its operation. Subsequently Notch shuts down all Wnt/beta-catenin signaling through nuclear export of an obligate beta-catenin transcriptional cofactor, thereby permanently channeling Wnt/beta-catenin signaling to endoderm and away from mesoderm.
- The response that pre-feeding sea urchin larvae make to reduce their arm lengths at high food density is mediated by dopamine signaling. Contrary to the prevailing theory, the default developmental program supports long arms to maximize food acquisition and phenotypic plasticity is mediated by food-induced dopamine signaling, which suppresses arm growth in order to conserve maternal energy reserves when food is abundant.