The Discovery of Noggin

Abstract

H ow does our nervous system develop? Half a century has passed since a Nobel Prize was awarded in this intriguing area of biology, yet the problem has not been solved. Recently published work appears to have many of the answers to this fascinating question. First, I'll provide a little background. In 1924, Hans Spemann and Hilda Mangold performed a classic experiment which later received a Nobel Prize. They showed that if a portion of a newt donor embryo was transplanted into a host newt embryo, twin embryos developed in the host embryo. The transplanted segment formation of a second nervous system, around which the other parts of the second embryo developed (Spemann 1938) (Figure 1). Spemann and Mangold termed the transplanted segment, which induced the new nervous system, the because it caused the organization of a second embryo. The Organizer itself was the dorsal lip of the blastopore, a region that eventually forms the notochord and associated structures. The dorsal lip moves from the exterior of the embryo to the interior and comes to rest under tissue that will become the nervous system (neural ectoderm tissue). Organizer tissue sends a or messages to the overlying ectoderm, telling it to differentiate into nervous tissue. This message has been termed the neural because it induces development in the ectoderm. Since Spemann and Mangold's findings, more than half a century has passed where investigators have unsuccessfully sought to identify and characterize the elusive inducer. It made sense that the inducer probably acts by directly or indirectly turning on genes that code for proteins that make the nervous system function. All sorts of interesting experiments were performed to try to identify the inducer. Some involved elegant approaches such as placing the dorsal lip (Organizer) in a droplet of saline, waiting for it to presumably release the inducer, then removing the dorsal lip tissue from the droplet, replacing it with a piece of ectoderm and observing whether differentiation takes place in the ectoderm (and it did) (Niu & Twitty 1953) (Figure 2). Many attempts followed to try to characterize the material in the droplet that was released by the dorsal lip and induced differentiation in ectoderm, but available technology did not result in definitive answers. Many other experiments were performed with confusing results. Johannes Holtfreter (1968) found that altered pH or ionic strength could result in differentiation in isolated ectoderm in the absence of the dorsal lip. But to everyone's amazement and, perhaps horror, many other agents also caused differentiation in ectoderm in the absence of the Organizer. This posed a gigantic dilemma. Holtfreter and others felt that all of the so-called inducers-which included high or low pH, variations in ionic strength, ground glass and methylene bluedamaged cells, and this damage (or sublethal cytolysis) resulted in differentiation (Holtfreter 1968; reviewed in Oppenheimer & Lefevre 1989). The molecular mechanisms involved in induction by abnormal inducers may be different from or in the same biochemical pathways that are involved in normal induction. Since so many abnormal substances could induce nervous tissue differentiation in ectoderm, very well-defined criteria had to be established to differentiate between the natural inducer and the imposters. The following key criteria were established to identify the authentic inducer (Lamb et al. 1993):