Nicole Le Douarin (original) (raw)

Professor Nicole Le Douarin

Citation delivered at the Annual Meeting, November 2002, by Professor Lewis Wolpert FRS FMedSci

Nicole Le Douarin is a Professor at the College de France and Secr�taire Perp�tuelle of the Acad�mie des Sciences de l'Institut de France. She came to science after being a high school teacher for eight years. She became fascinated by developmental biology through working with Professor Etienne Wolff who in 1958 suggested she research the development of the digestive tract in the chick. Her early papers, published whilst at the Institute at Nogent-sur-Marne, were on this topic. Then in 1969 there appeared in Compte Rendu a paper in French on the use of Japanese quail cells as biological markers in experimental embryology. It was the result of a chance event at the University of Nantes where she had been made an Associate Professor; she had been offered some quail eggs, by a geneticist there who had an excess of them. When she saw the quail nucleus in a section she recognised at once that it was different from that of the chick, and that quail tissue could be used to mark tissues and so follow their movement when grafted into the chick. She had already tried carbon particles and vital dyes to mark movements during morphogenesis. As Pasteur said: 'Fortune favours the prepared mind'.

The first experiment she did was to graft a neural tube of quail into the chick embryo to follow the migration of the neural crest. This discovery was to transform our understanding of the migration and development of neural crest and related tissues; it was brilliantly used by Le Douarin herself as well as by many other workers. Her other studies on development of the chick embryo, particularly gastrulation, nervous system, haematopoiesis, skull, and immune system, have also been outstanding.

Neural crest cells migrate from the boundary of the neural tube and give rise to a wide variety of tissues from dorsal root ganglia to bone and pigment cells, and Le Douarin has elucidated the mechanisms involved in this process. Culture of neural crest cells showed a striking heterogeneity of the population. In general it was shown that totipotent neural crest cells become progressively restricted, by a stochastic process, and also actively divide during their migration � the demonstration that environmental influences determined their fate was crucial.

The development of the autonomic ganglion cell precursors was influenced by environmental factors such as somite -derived structures. In the absence of the notochord and neural tube somite cells die, as do the local neural crest cells; the development of sensory ganglia is dependent on signals from the neural tube. The majority of the enteric nervous system (ENS) is derived from vagal neural crest cells (NCC). For many years, the contribution from a second region of the neuraxis (the sacral neural crest) to the ENS has been less clear, with conflicting reports appearing in the literature. To resolve this longstanding issue, Le Douarin's team documented the spatiotemporal migration and differentiation of vagal and sacral-derived NCC within the developing chick embryo using quail-chick grafting and antibody labelling. Results showed that vagal NCC colonised the entire length of the gut in a rostrocaudal direction. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Anterior cephalic neural crest is required for forebrain viability. In addition to pigment cells, and neural and endocrine derivatives, the neural crest is characterised by its ability to yield mesenchymal cells. In amniotes, this property is restricted to the cephalic region from the mid-diencephalon to the end of rhombomeres 8. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain.

Two mechanisms were shown to contribute to the formation of the neural tube in the chick. The conventional folding of the neural plate anteriorly and more caudal regression of Hensen's node bisects the ectoderm into two bilateral neural plates leaving in its wake the floor plate, notochord, and the dorsal endoderm. Neural chimeras showed that there is a common origin of the floor plate of the neural tube and the notochord from a group of cells localised in Hensen's node. Grafting of rhombomeres showed that their character as indicated by Hox gene expression could be altered if the rhombomeres was grafted from a rostral to a caudal position, but not if the graft was in the opposite direction. The inductive signal appears to come from the neural tube itself. Le Douarin's group also found that grafting brain primordia of pro and mes-encephalon from a mutant strain could transfer the susceptibility to epileptic seizures.

The neural crest contributes to the bones of the skull and her work demonstrated the precise origin from the mesectoderm, mesoderm, and somites. Cloning of the quail cDNA for mouse Hox 7 enabled her to show its expression in the ventral mesenchyme is similar to that in the mouse. In addition, physical linkage between chick Hox genes was established.

The somites give rise to both axial muscle and that which migrates into the limb. Using quail grafts, Le Douarin went on to illustrate that there are two lineages which give rise to these two different fates of muscle cells. Patterning of the somites along the D/V axis is influenced by signal from the floor plate and notochord which inhibit the development of dorsal structures, muscle and dermis. Sonic hedgehog, expressed ventrally in the tube and notochord, was shown to be required for the survival of both myogenic and chondrogenic lineages. Lateral somite specification comes from signals including BMP 4 from the lateral plate. The somites themselves, together with the lateral somatopleure, determine the dorso/ventral polarity of the limb.

By grafting bursal rudiments and limb buds of quail into chick and vice versa Le Douarin made clear that the whole haemopoietic population of the bursa of Fabricius is derived from blood borne extrinsic stem cells. Studies on the immune system showed the importance of the embryonic thymus epithelium in determining whether a foreign graft to the early embryo would be rejected.

Professor Le Douarin's work has had an enormous influence on developmental biology. Her numerous students and collaborators at Nogent where she became director in 1975 have also made very significant contributions that have had important implications for a variety of medical problems particularly congenital abnormalities, haematopoiesis, and the immune system. It is more than fitting that we welcome her today as an Honorary Fellow of the Academy of Medical Sciences.