Genetic analysis of vertebrate CNS development

Dr. Monaghan’s laboratory is interested in defining the molecular and cellular mechanisms that determine cell fate in the central nervous system and how disruption of these events leads to behavioral abnormalities. Relatively few genes have been identified which control development of structures within the brain that are essential for emotion and cognition. Dr. Monaghan and colleagues have cloned a number of genes in mice that show restricted patterns of expression in the developing brain. These genes code for transcription factors which are proposed to regulate key events in neurogenesis. Using genetic engineering, two of these genes, tailless and Spalt, have recently been mutated in mice. Tailless mutant animals exhibit profound behavioral abnormalities including poor cognition, hyperexcitibility, and severe aggressiveness. Spalt mutant animals do not feed and therefore die perinatally. In the future, this laboratory would like to use these animals to (1) analyze in more detail the developmental events at the molecular and cellular level that lead their respective phenotypes, (2) characterize the roles of these genes in the development of the nervous system and define the specific molecular pathways disrupted in these animals; (3) create temporally and spatially regulated conditional mutations in mice and decipher their anatomical and behavioral consequences, and, (4) clone additional novel genes required for the formation/function of the mammalian brain.

Trainees have the opportunity to learn a variety of molecular and cellular techniques including gene cloning and characterization, genetic engineering in mice, production and handling of transgenic animals, embryology, in vivo and in vitro cell culture and manipulation, immunohistochemistry, in situ hybridization, and analysis of behavior in mice.

Monaghan, A.P., Grau, E., Bock, D., and Schuetz, G. The mouse homolog of the nuclear receptor tailless is expressed in the developing forebrain. Development 121: 839-853, 1995.

Ott, T., Kaestner, K.H., Monaghan, A.P., and Schuetz, G. The mouse homolog of the region specific homeotic gene Spalt of drosophilia is expressed in the developing nervous system and in mesoderm derived structures. Mech. Dev. 56: 117-128, 1996.

Kellendonk, C., Tronche, F., Monaghan, A.P., Angrand, P.O., Stewart, F., and Schuetz, G. Regulation of Cre recombinase activity by the synthetic steroid RU486. Nucleic Acid Research 24: 1404-1411, 1996.

Monaghan, A.P., Bock, D., Gass, P., Schwaeger, A., Wolper, D.P., Lipp, H-P., and Schuetz, G. Defective limbic system in mice lacking the tailless gene. Nature 390: 515-517, 1997.

Glinka, A., Wu, W., Delius, H., Monaghan, A.P., Blumenstock, C., and Niehrs, C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391: 357-362, 1998.

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