Location and size of dopaminergic and serotonergic cell populations are controlled by the position of the midbrain-hindbrain organizer.

Midbrain dopaminergic and hindbrain serotonergic neurons play an important role in the modulation of behavior and are involved in a series of neuropsychiatric disorders. Despite the importance of these cells, little is known about the molecular mechanisms governing their development. During embryogenesis, midbrain dopaminergic neurons are specified rostral to the midbrain-hindbrain organizer (MHO), and hindbrain serotonergic neurons are specified caudal to it. We report that in transgenic mice in which Otx2 and accordingly the MHO are shifted caudally, the midbrain dopaminergic neuronal population expands to the ectopically positioned MHO and is enlarged. Complementary, the extension of the hindbrain serotonergic cell group is decreased. These changes are preserved in adulthood, and the additional, ectopic dopaminergic neurons project to the striatum, which is a proper dopaminergic target area. In addition, in mutants in which Otx2 and the MHO are shifted rostrally, dopaminergic and serotonergic neurons are relocated at the newly positioned MHO. However, in these mice, the size ratio between these two cell populations is changed in favor of the serotonergic cell population. To investigate whether the position of the MHO during embryogenesis is also of functional relevance for adult behavior, we tested mice with a caudally shifted MHO and report that these mutants show a higher locomotor activity. Together, we provide evidence that the position of the MHO determines the location and size of midbrain dopaminergic and hindbrain serotonergic cell populations in vivo. In addition, our data suggest that the position of the MHO during embryogenesis can modulate adult locomotor activity.

Effects of follistatin and BMP4 proteins on early dorso-ventral patterning in chick.

In Xenopus and zebrafish certain bone morphognetic proteins (BMPs), and proteins that antagonise these by preventing their interaction with receptors, constitute a morphogen system in primary dorso-ventral patterning. This system may be directly involved in the parallel processes, within mesoderm and ectoderm, whereby the boundaries of the dorsal (paraxial) mesoderm and the neural plate are established. The bird blastoderm, amenable to grafting techniques and to direct exposure to specific proteins, has provided an opportunity to explore the phylogenetic conservation of such antagonistic system. We have grafted the gastrular organiser (node) into hosts, testing the effects of prior exposure of either grafted or host tissue to Follistatin (a known antagonist of TGFbeta superfamily ligands including BMP4) or to BMP4 protein. Strong, converse effects are seen from the two agents, the most consistent being on the sizes of new dorsalised areas (second neural plates) induced in host epiblast. Follistatin also enhances extension movements due to grafts, though without clear effect upon the rostro-caudal completeness of new patterns. Neural induction in chick epiblast by grafted mouse nodes are also more extensive, after their pre-incubation in Follistatin. Follistatin potentiates other, unknown but distinctive signals coming from the node, being unable to convert other non-inducing pieces of blastoderm into organisers on grafting. Pre-incubation of early blastoderms in BMP4 has such profound effects on normal dorsal axial development that host responsiveness of these blastoderms as hosts to node grafts is difficult to assess. Follistatin has no such overt effect on host development, but greatly enhances the competence of host epiblast to grafts of untreated nodes. Early chick BMP4 and BMP7 expressions are consistent with the proposed roles, though Follistatin is probably an experimental tool only in the present study.