The morphogenesis of the brain and the differentiation of the neural structures are highly complex processes. A series of temporally and spatially regulated morphogenetic events gives rise to smaller areas that are phylogenetically, functionally and often morphogenetically different. Candidate genes for positional information and differentiation during morphogenesis have been isolated. Both in vivo inactivation in mice and impairment in human diseases revealed, that they are required in regional specification and/or correct cell-type induction. We have previously cloned and characterized the murine Otx1 gene, which is related to orthodenticle (otd), a homeobox-containing gene required for Drosophila head development. Expression data during murine embryogenesis and postnatal brain development support the idea that Otx1 could be required for correct brain and sense organs development. To decipher its role in vivo we produced null mice by replacing Otx1 with the lacZ gene. Otx1-/- mice showed spontaneous epileptic behaviour and multiple abnormalities affecting mainly the telencephalic temporal and perirhinal areas, the hippocampus, the mesencephalon and the cerebellum, as well as the acoustic and visual sense organs. Our findings indicate that the Otx1 gene product is required for proper brain functions.

To investigate the embryonic development of the central nervous system of the lamprey Lampetra fluviatilis, we have isolated and analysed the expression patterns of members of the LIM-homeodomain, Pax, Hedgehog and Nkx2.1 families. Using degenerate RT-PCR, single representatives of Lhx1/Lhx5, Lhx2/Lhx9, Pax3/Pax7 and Hedgehog families could be isolated in L. fluviatilis. Expression analysis revealed that the lamprey forebrain presents a clear neuromeric pattern. We describe the existence of 4 embryonic diencephalic prosomeres whose boundaries can be identified by the combined and relative expressions of LfPax37, LfLhx15 and LfLhx29. This suggests that the embryonic lamprey and gnathostome forebrain are patterned in a highly similar manner. Moreover, analysis of the LfHh gene, which is expressed in the hypothalamus, zona limitans intrathalamica and floor plate, reveals the possible molecular origin of this neuromeric brain pattern. By contrast, LfHh and LfNkx2.1 expressions suggest major differences in patterning mechanisms of the ventral telencephalon when compared to gnathostomes. In summary, our findings highlight a neuromeric organisation of the embryonic agnathan forebrain and point to the possible origin of this organisation, which is thus a truly vertebrate character. They also suggest that Hh/Shh midline signalling might act as a driving force for forebrain evolution.

The hypothalamus has been a central topic in neuroanatomy because of its important physiological functions, but its mature organization remains elusive. Deciphering its embryonic and adult organization is crucial in an evolutionary approach of the organization of the vertebrate forebrain. Here we studied the molecular organization of the hypothalamus and neighboring telencephalic domains in a cartilaginous fish, the catshark, Scyliorhinus canicula, focusing on ScFoxg1a, ScShh, ScNkx2.1, ScDlx2/5, ScOtp, and ScTbr1 expression profiles and on the identification α-acetylated-tubulin-immunoreactive (ir), TH-ir, 5-HT-ir, and GFAP-ir structures by means of immunohistochemistry. Analysis of the results within the updated prosomeric model framework support the existence of alar and basal histogenetic compartments in the hypothalamus similar to those described in the mouse, suggesting the ancestrality of these subdivisions in jawed vertebrates. These data provide new insights into hypothalamic organization in cartilaginous fishes and highlight the generality of key features of the prosomeric model in jawed vertebrates.