A. Paula Monaghan-Nichols, PhD

Associate Professor, Neurobiology

Contact

Biomedical Science Tower 3, Room 6065
412-648-1856
F: 412-648-1441
monaghan@pitt.edu

Education

PhD, MRC Human Genetics Unit, Edinburgh, Scotland (1990)

Focus

Genetic analysis of vertebrate CNS development.

Research Summary

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. Two key transcription factors, tailless and Spalt, have recently been mutated in mice. Absence of these genes leads to early abnormalities in the patterns of neuronal differentiation in the cerebral cortex in mice. Tailless mutant animals also exhibit profound behavioral abnormalities including poor cognition, epilepsy, and severe aggressiveness. Spalt mutant animals die perinatally due to kidney deficits. We have rescued this phenotype by restricting deletion of the Sall genes to the cerebral cortex. Mice survive and exhibit behavioral abnormalities. 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) define the specific molecular pathways disrupted in these animals; (3) create temporally and spatially regulated conditional mutations in mice using cre-recombinase (4) manipulate the levels of both gene during development using in-vitro electroporations. The anatomical and behavioural consequences of these disruptions will be analyzed at the cellular, molecular and behavioural level.

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.

Publications

Harrison, S.J., Nishinakamura, R. and Monaghan, A.P. Sall1 regulates mitral cell development and olfactory nerve extension in the developing olfactory bulb. Cereb. Cortex. 18(7): 1604-17, 2008.

Harrison, S.J., Parrish, M. and Monaghan, A.P.. Sall3 is required for the terminal differentiation of dopaminergic olfactory interneurons. J. Comp. Neurol. 507(5): 1780-1794, 2008.

Roy, K., Kuznicki, K., Wu, Q., Sun, Z., Bock, D., Schutz, G., Vranich, N. and Monaghan, A.P. The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex. J. Neurosci. 24(38): 8333-45, 2004.

Parrish, M., Ott, T., Lance-Jones, C., Schuetz, G., Schwaeger-Nickolenko, A. and Monaghan, A.P. Loss of the mouse Sall3 gene leads to abnormalities in cranial nerves, palate deficiency and perinatal lethality. Mol. Cell Biol. 24(16): 7102-12, 2004.

Land, P.W. and Monaghan, A.P. Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. Cereb. Cortex. 13(9): 921-31, 2003.

Roy, K., Thiels, E. and Monaghan, A.P. Loss of the tailless gene affects forebrain development and emotional behavior. Physiol. Behav. 77(4-5): 595-600, 2002.

Ott, T., Parrish, M., Bond, K., Schwaeger-Nickolenko, A. and Monaghan, A.P. A new member of the spalt like zinc finger protein family, msal-3, is expressed in the CNS and sites of epithelial/mesenchymal interaction. Mech. Dev. 101 (1-2): 203-207, 2000.