Sunday, April 28, 2024
4/28/2024
Project Summary/Abstract The proposed project is focused on the mechanism controlling posterior elongation of the vertebrate embryo, a process which is still poorly understood. In amniotes such as birds or mammals, the embryonic body forms sequentially in a head-to-tail sequence. Progressively more posterior territories are laid in the wake of regression movements of the primitive streak and tail bud (TB) [1]. Unlike anterior regions which mostly depend on convergence extension, posterior elongation of the embryonic body of amniotes relies on volumetric growth. Our past work showed how the paraxial mesoderm, which forms the skeletal muscles and vertebrae, drives these posterior elongation movements [2]. We demonstrated that a posterior-to-anterior gradient of FGF signal- ing established in the most posterior region of the paraxial mesoderm (called presomitic mesoderm (PSM)) im- poses a parallel gradient of random cell motility in this tissue. This gradient is necessary for posterior elongation of the embryo. Our findings led us to propose that the PSM can generate posteriorly oriented compression forces that trigger axial elongation in response to the FGF gradient [3]. Indeed, we demonstrated that an isolated PSM can generate FGF-dependent elongation forces when confined in a PDMS microchannel [4]. Our preliminary data demonstrated that the extracellular volume (EV) is increased in the posterior PSM compared to the anterior. We showed that hyaluronic acid (HA), a naturally occurring polymer composed of repeating disaccharides, is an important component of the PSM extracellular matrix required for PSM elongation [4]. Together, our results sug- gest a model whereby FGF promotes cell motility, triggering an HA-dependent increase in EV, generating com- pression forces extending the embryo posteriorly. Here, we will investigate the role of HA in embryonic elongation. We will combine in vivo experiments in the chicken embryo with in vitro studies in novel human iPS-derived PSM organoids that we recently established [5]. We will first analyze how HA signals to PSM cells to control their motility in vivo in the chicken embryo. We will then examine whether this plays a role in the control of the EV. We will also leverage our novel system of human iPS-derived PSM organoids (called segmentoids), which form elongated structures recapitulating PSM development [5]. This system offers the possibility to genetically manipulate iPS cells and provides the unprec- edented opportunity to explore the role of HA in the control of PSM elongation. Finally, we will use a comple- mentary 3D model of human iPS-derived somites (called somitoids) to probe HA’s role in PSM epithelialization and somite formation. Our studies will shed light on the process of axis elongation and elucidate the role of HA, a poorly studied ubiquitous glycosaminoglycan, in this morphogenetic process. This work will be informative about human malformations associated to defective axis formation, such as caudal agenesis or spina bifida [6].
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
