Seminar

TGFb family signal interpretation in development and disease

Danny Huylebroeck

To understand the genetic and molecular control of instructed cell differentiation in the first place, but possibly cell plasticity as well, we have always studied the TGFbeta/BMP/Nodal-Activin signaling system. Initially we did this in early embryogenesis and subsequent organogenesis in mice, and more recently included (often challenged) adult mice as well as cultured pluripotent stem cells (ESCs, iPSCs). Over many years, our approaches of perturbation of single or more system components, followed by phenotyping, fully confirmed the key principle of aberrant developmental signaling in congenital and chronic disease, and defective cell-based repair in tissues and organs. This will be illustrated in brief for BMP type-I receptors and BMP-Smads and, in more detail, for the Smad-interacting, Mowat-Wilson Syndrome transcription factor (and EMT regulator) Zeb2. Seen the pleiotropic nature of this signaling system and our follow-the-phenotype attitude, many developmental events as well as organ systems can thus be passed in review. This seminar selected forebrain development and adult neurogenesis (Zeb2), together with a new therapeutic option for glioblastoma; cardiac Ebstein anomaly (BMPR-IA) and protective effects after infarct (Zeb2); and ovarian cancer (BMPR-IA/B, Smad1/5) and primary and metastatic melanoma (Zeb2). At the same time, the unmistakable need for thorough biochemical/multi-omics based studies of component-dependent and regulated target genes, as well as partner-dependent mechanisms of action (with Zeb2 as example) will become evident.