Pitx2, a homeobox transcription factor, was originally identified in the investigators' laboratory as an important regulator of early embryonic development [1]. Humans with mutations in PITX2 exhibit Rieger syndrome, a haploinsufftciency disorder with eye, tooth, and umbilical defects, and variable cardiac, pituitary, and brain malformations including mental retardation and hydrocephalus. The investigators have shown that mice with genetically engineered reductions in Pitx2 expression exhibit dosage-dependent abnormalities in the eye, pituitary, heart, and abdominal organs suggestive of aberrant cellular proliferation, differentiation, or migration [41, 42]. Central nervous system (CNS) defects in Pitx2 mice include abnormalities in the developing neural tube and diencephalon, which the investigators propose to further characterize. In the mouse CNS, Pitx2 is expressed in the developing neuroepithelial ventricular zone, in radially migrating cells, and in the mature cortex, mesencephalon, and diencephalon [72, 101]. In this proposal, the investigators will define the role of Pitx2 in the mouse central nervous system, with a focus on progenitor cell proliferation and differentiation in the diencephalon. Using Cre/loxP site- specific recombination in genetically engineered mice, they will characterize the effects of Pitx2 loss and gain of function on CNS progenitor cell proliferation and differentiation. This proposal integrates the PI previous experience using in vitro models of neuronal development with a training program in whole animal genetic approaches to understanding genetic mechanisms of CNS development. Results of these experiments will contribute to our understanding of Pitx2 in mental retardation, in patterning the normal and Pitx2 mutant CNS, and in delineating Pitx2 molecular pathways involved in CNS stem cell fate determination.
Three aims are proposed: 1) Characterize Pitx2 expression in the developing (E8.5-14.5) mouse diencephalon, 2) Develop and analyze mice with Pitx2 loss of function, and 3) Develop and analyze transgenic mice with CNS-specific Pitx2 gain of function.
| Skidmore, Jennifer M; Cramer, John D; Martin, James F et al. (2008) Cre fate mapping reveals lineage specific defects in neuronal migration with loss of Pitx2 function in the developing mouse hypothalamus and subthalamic nucleus. Mol Cell Neurosci 37:696-707 |
| Sclafani, Anthony M; Skidmore, Jennifer M; Ramaprakash, Hemanth et al. (2006) Nestin-Cre mediated deletion of Pitx2 in the mouse. Genesis 44:336-44 |
| Philips, Steven T; Albin, Roger L; Martin, Donna M (2005) Genetics of subthalamic nucleus in development and disease. Exp Neurol 192:320-30 |
| Martin, Donna M; Skidmore, Jennifer M; Philips, Steven T et al. (2004) PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain. Dev Biol 267:93-108 |
| Probst, Frank J; Hedera, Peter; Sclafani, Anthony M et al. (2004) Skewed X-inactivation in carriers establishes linkage in an X-linked deafness-mental retardation syndrome. Am J Med Genet A 131:209-12 |
| Treutelaar, Mary Kay; Skidmore, Jennifer M; Dias-Leme, Claudia L et al. (2003) Nestin-lineage cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 52:2503-12 |
| Martin, Donna M; Raphael, Yehoash (2003) Gene-based diagnostic and treatment methods for tinnitus. Int Tinnitus J 9:3-10 |
| Martin, Donna M; Probst, Frank J; Fox, Sharon E et al. (2002) Exclusion of PITX2 mutations as a major cause of CHARGE association. Am J Med Genet 111:27-30 |
| Martin, Donna M; Skidmore, Jennifer M; Fox, Sharon E et al. (2002) Pitx2 distinguishes subtypes of terminally differentiated neurons in the developing mouse neuroepithelium. Dev Biol 252:84-99 |
