Developmental gene control of brainstem function: views from the embryo.

The respiratory rhythm is generated within the hindbrain reticular formation, rostrally in the vicinity of the facial nucleus and caudally within the vagal/glossopharyngeal domain. This is probably one of the best models to understand how genes have been selected and conserved to control adaptive behaviour in vertebrates. The para-facial region is well understood with respect to the transcription factors that underlie antero-posterior specification of neural progenitors in the embryo. Hox paralogs and Hox-regulating genes kreisler and Krox-20 govern transient formation of developmental compartments, the rhombomeres, in which rhythmic neuronal networks develop. Hox are master genes selecting and coordinating the developmental fate of reticular and motor neurons thereby specifying patterns of motor activities operating throughout life. Neuronal function and development are also tightly linked in the vagal/glossopharyngeal domain. At this level, bdnf acts as a neurotrophin of peripheral chemoafferent neural populations and as a neuromodulator of the central rhythmogenic respiratory circuits. A general view is now emerging on the role of developmental transcription and trophic factors allowing the coordinated integration of different neuronal types to produce, and eventually refine, respiratory rhythmic pattern in a use-dependent manner.

Comparison of even-skipped related gene expression pattern in vertebrates shows an association between expression domain loss and modification of selective constraints on sequences.

The even-skipped related genes (evx) encode homeodomain-containing transcription factors that play key roles in body patterning and neurogenesis in a wide array of Eumetazoa species. It is thought that the genome of the last common ancestor of Chordata contained a unique evx gene linked to a unique ancestral Hox complex. During subsequent evolution, two rounds of whole genome duplication followed by individual gene losses gave rise to three paralogs: evx1, evx2, and eve1. Then, eve1 was maintained in Actinopterygii lineage but not in Tetrapoda. To explain this discrepancy, we examined the expression patterns of the evx1 homologue, Xhox3, in Xenopus laevis and that of evx1 and eve1 in Danio rerio. We show here that Xhox3 is expressed in a manner that closely reflects the inferred expression pattern of the evx1 gene in the last common ancestor of Vertebrata (i.e., in gastrula, the central nervous system, the posterior gut, and the tip of the growing tail). Zebrafish evx1 and Xenopus Xhox3 are expressed in homologous cell lineages of the central nervous system and of the posterior gut, but evx1 was undetectable in the gastrula and the tail bud. Strikingly, eve1 is the only evx gene of zebrafish to be expressed in these two latter regions. Thus, the ancestral expression pattern of evx1 in vertebrates appears to have been distributed between evx1 and eve1 in zebrafish. We propose that evx1 and eve1 underwent a complementary loss of expression domain in zebrafish that allowed the maintenance of the two paralogs in accordance with the duplication-degeneration-complementation model. It is important to note that, in zebrafish, Evx1 and Eve1 have lost most of the protein domain upstream of the homeodomain. In addition, Eve1 has accumulated substitutions in positions that are highly conserved in all other Evx proteins. Thus, the reduction of the expression domain of both evx1 and eve1 in zebrafish appears to be associated with the modification of constraints on the protein sequences, allowing the shortening of both genes and an accelerated substitution rate in eve1.

From hindbrain segmentation to breathing after birth: developmental patterning in rhombomeres 3 and 4.

Respiration is a rhythmic motor behavior that appears in the fetus and acquires a vital importance at birth. It is generated within central pattern-generating neuronal networks of the hindbrain. This region of the brain is of particular interest since it is the most understood part with respect to the cellular and molecular mechanisms that underlie its development. Hox paralogs and Hox-regulating genes kreisler/mafB and Krox20 are required for the normal formation of rhombomeres in vertebrate embryos. From studies of rhombomeres r3 and r4, the authors review mechanisms whereby these developmental genes may govern the early embryonic development of para-facial neuronal networks and specify patterns of motor activities operating throughout life. A model whereby the regional identity of progenitor cells can be abnormally specified in r3 and r4 after a mutation of these genes is proposed. Novel neuronal circuits may develop from some of these misspecified progenitors while others are eliminated, eventually affecting respiration and survival after birth.