Rnd3 is necessary for the correct oligodendrocyte differentiation and myelination in the central nervous system.

Rho small GTPases are proteins with key roles in the development of the central nervous system. Rnd proteins are a subfamily of Rho GTPases, characterized by their constitutive activity. Rnd3/RhoE is a member of this subfamily ubiquitously expressed in the CNS, whose specific functions during brain development are still not well defined. Since other Rho proteins have been linked to the myelination process, we study here the expression and function of Rnd3 in oligodendrocyte development. We have found that Rnd3 is expressed in a subset of oligodendrocyte precursor cells and of mature oligodendrocytes both in vivo and in vitro. We have analyzed the role of Rnd3 in myelination using mice lacking Rnd3 expression (Rnd3gt/gt mice), showing that these mice exhibit hypomyelination in the brain and a reduction in the number of mature and total oligodendrocytes in the corpus callosum and striatum. The mutants display a decreased expression of several myelin proteins and a reduction in the number of myelinated axons. In addition, myelinated axons exhibit thinner myelin sheaths. In vitro experiments using Rnd3gt/gt mutant mice showed that the differentiation of the precursor cells is altered in the absence of Rnd3 expression, suggesting that Rnd3 is directly required for the differentiation of oligodendrocytes and, in consequence, for the correct myelination of the CNS. This work shows Rnd3 as a new protein involved in oligodendrocyte maturation, opening new avenues to further study the function of Rnd3 in the development of the central nervous system and its possible involvement in demyelinating diseases.

Role of Shh in the development of molecularly characterized tegmental nuclei in mouse rhombomere 1.

Hindbrain rhombomeres in general are differentially specified molecularly by unique combinations of Hox genes with other developmental genes. Rhombomere 1 displays special features, including absence of Hox gene expression. It lies within the hindbrain range of the Engrailed genes (En1, En2), controlled by the isthmic organizer via diffusion of FGF8. It is limited rostrally by the isthmus territory, and caudally by rhombomere 2. It is double the normal size of any other rhombomere. Its dorsal part generates the cerebellar hemispheres and its ventral part gives rise to several populations, such as some raphe nuclei, the interpeduncular nucleus, the rhabdoid nucleus, anterior, dorsal, ventral and posterodorsal tegmental nuclei, the cholinergic pedunculopontine and laterodorsal tegmental nuclei, rostral parts of the hindbrain reticular formation, the locus coeruleus, and part of the lateral lemniscal and paralemniscal nuclei, among other formations. Some of these populations migrate tangentially before reaching their final positions. The morphogen Sonic Hedgehog (Shh) is normally released from the local floor plate and underlying notochord. In the present report we explore, first, whether Shh is required in the specification of these r1 populations, and, second, its possible role in the guidance of tangentially migrating neurons that approach the midline. Our results indicate that when Shh function is altered selectively in a conditional mutant mouse strain, most populations normally generated in the medial basal plate of r1 are completely absent. Moreover, the relocation of some neurons that normally originate in the alar plate and migrate tangentially into the medial basal plate is variously altered. In contrast, neurons that migrate radially (or first tangentially and then radially) into the lateral basal plate were not significantly affected.

Mesencephalic neuronal populations: new insights on the ventral differentiation programs.

The midbrain is a complex structure where different functions are located. This formation is mainly involved in the visual and auditory information process (tectum) and visual movements and motor coordination (tegmentum). Here we display a complete description of midbrain anatomy based on the prosomeric model and of the developmental events that take place to generate this structure. We also summarize the new data about the differentiation and specification of the basal populations of the midbrain. The neural tube suffers the influence of several secondary organizers. These signaling centers confer exact positional information to the neuroblasts. In the midbrain these centers are the Isthmic organizer for the antero-posterior axis and the floor and roof plates for the dorso-ventral axis. This segment of the brain contains, in the dorsal part, structures such as the collicula (superior and inferior), tectal grey and the preisthmic segment, and in the basal plate, neuronal populations such as the oculomotor complex, the dopaminergic substantia nigra and the ventral tegmental area, the reticular formation and the periacueductal grey. Knowledge of the genetic cascades involved in the differentiation programs of the diverse populations will be extremely important to understand not only how the midbrain develops, but how degenerative pathologies, such as Parkinson's disease, occurs. These cascades are triggered by signaling molecules such as Shh, Fgf8 or Wnt1 and are integrated by receptor complexes and transcription factors. These are directly responsible for the induction or repression of the differentiation programs that will produce a specific neuronal phenotype.