Our Science – Kuehn Website
Michael R. Kuehn, Ph.D.
Genetic Control of Vertebrate Embryonic Development
Our research program is focused on basic mechanisms underlying the development of the mammalian embryo, with a goal toward understanding how aberrant regulation of developmentally important inter- and intra-cellular signaling pathways leads to human disease.
Over the course of embryonic development progenitor cells proliferate, differentiate and migrate thereby giving rise to hundreds of discrete cell types each with a distinct location, function and gene expression profile. This process is regulated by a small number of intercellular signaling pathways that are used repeatedly during development. Research in our laboratory has long been focused on the pathway regulated by Nodal, a secreted Transforming Growth Factor (TGF) β related ligand. Our work has helped define the molecular components of the pathway and shown that Nodal signaling is required for the germ layers - mesoderm, endoderm and ectoderm - to form and be properly organized within the body. Nodal signaling also is implicated in stem cell biology and cancer. Thus a detailed understanding of this pathway is essential not only for understanding how cells in the embryo become committed to specific cell fates, but also to provide insight into cancer progression, central to the mission of the National Cancer Institute.
Our ongoing work on Nodal is divided into two major efforts. The first involves examining the role of Nodal signaling directly in the embryo, using conditional mutagenesis and confocal imaging techniques to study Nodal function in different lineages arising at different developmental stages. One key recent finding we have obtained is that loss of Nodal specifically from the mesoderm and endoderm newly arising at gastrulation results only in left-right body axis defects, arguing that essential developmental functions in organogenesis are complete by this early stage. In other work, we have found that even earlier deletion from the visceral endoderm, an extra-embryonic lineage, delays or abrogates the directional migration of the distal visceral endoderm. This work expands our understanding of Nodal function in establishing the main anterior-posterior axis, and clarifies the significant role played by Nodal expressed specifically within visceral endoderm cells.
Our second major effort on Nodal addresses the important question of how this developmental signaling pathway interfaces with epigenetic gene regulatory mechanisms. We recently have discovered that Nodal signaling regulates the recruitment of the histone demethylase Jmjd3 to Nodal target loci to counteract the Polycomb repressive complex. This finding provides significant new insight into how Nodal signals control target gene expression, and potentially impacts our understanding of how Nodal can function both in maintaining pluripotency of stem cells and in driving differentiation along specific lineages.
It is now clear that the ubiquitin proteasome system plays a major role in development. This is well illustrated by its impact on signaling by TGF-β and related proteins, including Nodal. The importance of the ubiquitin like protein SUMO in development is also emerging. Research in our laboratory has shown that aberrations in SUMO deconjugation have consequences for development. Given the number of SUMO target proteins that play roles in critical nuclear processes it is not surprising that sumoylation has been implicated in cancer. Thus, a detailed understanding of SUMO function is of importance for our understanding both of normal growth and development as well as malignant transformation.
Our ongoing work on SUMO is divided into two major efforts. The first involves examining the role of the desumoylating enzyme SENP1 in placental development. We study a mutant allele of the Senp1 gene that arose in a retroviral insertional mutagenesis screen. When homozygous this mutant allele leads to defects in the labyrinth layer of the placenta, associated with abnormal proliferation and differentiation of placental trophoblast stem cells. We have found cell cycle defects in primary trophoblast stem cell cultures and are using this tissue culture model system to unravel how desumoylation regulates the trophoblast cell cycle.
Our second major effort addresses the important question of redundancy vs. specificity in the SUMO system. There are three functional SUMO proteins found in higher eukaryotes, including the almost identical SUMO2 and SUMO3 and the more distantly related SUMO1. We have generated and characterized SUMO1 mutant mice, making the surprising finding that SUMO1 is dispensable for normal development and homeostasis. We have also generated mice mutant for SUMO3. Having this resource provides us a unique opportunity to define the distinct and shared functions of the different SUMO proteins in the developing and adult organism.
This page was last updated on 2/20/2013.