Preliminary data have shown that homozygous mutant mice for the engrailed genes are deficient in the noradrenergic locus coeruleus, the dopaminergic cell groups A8, A9 and A10 and the serotonergic dorsal raphe nucleus. The distribution of these cells will be examined in more details in animals heterozygous for one of the engrailed gene, but homozygous for the other to reveal a possible gene dose effect on the development of the posterior midbrain and anterior hindbrain. Further, the subcortical, retinocollicular, pontine cerebellar and olivocerebellar projections will be investigated in these mutant mice.
The second aim of the study will be to examine if the engrailed genes are directly responsible for the development of the dopaminergic and serotinergic neurons in the midbrain and hindbrain. I hypothesize that the expression of En-1 and En-2 confers upon a precursor population a capacity to respond to the floor plate inductive signal and generate dopaminergic (and possibly serotonergic and noradrenergic) neurons. To test this, recombinant replication-competent retroviruses containing En-1 or En-2 cDNA will be used to misexpress these genes in parts of the developing brain which normally do not contain any dopaminergic.
| Simon, Horst H; Scholz, Christian; O'Leary, Dennis D M (2005) Engrailed genes control developmental fate of serotonergic and noradrenergic neurons in mid- and hindbrain in a gene dose-dependent manner. Mol Cell Neurosci 28:96-105 |
| Simon, H H; Saueressig, H; Wurst, W et al. (2001) Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 21:3126-34 |
