The bone morphogenetic proteins (Bmps) and Wnts represent two families of signaling proteins that are fundamental regulators of development. In the telencephalon - the forebrain subdivision that contains the cerebral cortex - multiple Bmps and Wnts are expressed in the dorsal midline region (DMR), where they are likely responsible for multiple developmental functions and malformation phenotypes. However, their presumed roles have remained elusive, due in part to significant functional redundancy among family members. This and other factors have greatly minimized the impact of traditional mouse genetics on elucidating Bmp and Wnt functions in telencephalic development. To overcome this limitation, we have adopted an alternative, but well established, genetic approach - lineage-specific cellular ablation. In our recently improved system, we utilize the restricted expression of a Bmp family member (Gdf7) to ablate a small subset of DMR cells in living mouse embryos. This causes marked reductions of multiple Bmp and Wnt signals, which are associated with three major defects in the telencephalon: 1) Loss of choroid plexus, the producer of cerebrospinal fluid, 2) selective cortical patterning defects, and 3) holoprosencephaly (HPE), the most common congenital malformation of the human brain. The central hypothesis driving this proposal is that DMR-dependent functions in telencephalic patterning and HPE pathogenesis are mediated by Bmp and Wnt signals. The immediate goal is to determine whether Bmp and Wnt signals are necessary and sufficient to mediate the embryonic patterning functions of the DMR. We will address this hypothesis by combining mouse genetics with explant cultures, which will be analyzed with markers and quantitative gene expression studies. K02 career development activities focus on developing a comprehensive explant approach and new DMR ablation models that allow for postnatal survival. Other personnel will consult and provide relevance to human HPE. These activities should facilitate the candidate's long-term goal of developing a research program that answers fundamental questions in early telencephalic development and disease. The insights into human HPE provide immediate relevance to public health. In addition, this project should lay the groundwork for understanding other human brain disorders that involve Bmp and Wnt signals. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02NS053511-02
Application #
7152936
Study Section
NST-2 Subcommittee (NST)
Program Officer
Riddle, Robert D
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$160,562
Indirect Cost
Name
University of California Irvine
Department
Pathology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Hu, Jia Sheng; Doan, Linda T; Currle, D Spencer et al. (2008) Border formation in a Bmp gradient reduced to single dissociated cells. Proc Natl Acad Sci U S A 105:3398-403
Mangale, Vishakha S; Hirokawa, Karla E; Satyaki, Prasad R V et al. (2008) Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate. Science 319:304-9
Monuki, Edwin S (2007) The morphogen signaling network in forebrain development and holoprosencephaly. J Neuropathol Exp Neurol 66:566-75
Cheng, Xun; Hsu, Ching-mei; Currle, D Spencer et al. (2006) Central roles of the roof plate in telencephalic development and holoprosencephaly. J Neurosci 26:7640-9