The wheels mutation in the mouse causes vascular, inner ear and hindbrain defects / Alireza Alavizadeh.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Alavizadeh, Alireza.

Contributor:

Bucan, Maja, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

xi, 265 pages : illustrations ; 29 cm

Production:

2001.

Summary:

Phenotype-based random mutagenesis screens provide a powerful tool for identification of single-gene mutations and systematic determination gene function. In a screen for mouse mutations with dominant behavioral anomalies, we identified Wheels, a mutation associated with circling and hyperactivity in heterozygotes and embryonic lethality in homozygotes. The Wheels locus has been mapped to the 1.1 cM region between D4Mit104 and D4Mit181 in the centromeric portion of mouse chromosome 4. Homozygous mutant Wheels embryos die at E10.5--E11.5 and exhibit a host of morphological anomalies which include growth retardation, truncation of the forebrain and defective angiogenesis. PECAM-1 staining of embryos revealed normal formation of the primary vascular plexus or vasculogenesis, whereas subsequent stages of branching and remodeling or angiogenesis is abnormal in the yolk sac and in the embryo proper. To obtain insights into the circling behavior, we examined development of the inner ear by paint-filling of membranous labyrinths of Whl /+ embryos. This analysis revealed truncation or absence of lateral, and in some cases posterior, semicircular canals from E12.5. Marker analysis revealed an early molecular phenotype in heterozygois embryos characterized by perturbed expression of bone morphogenetic protein 4 (Bmp4) and Msx-1 (Msx1) in lateral and posterior cristae at E11.5.

We have accomplished several goals in our genetic and developmental analysis of the Wheels mutation. The generation of a high resolution genetic map of the Wheels locus provides a foundation for positional cloning of the Wheels mutation through physical mapping and candidate gene analysis. Although we did not isolate the primary genetic lesion in Wheels, our molecular and phenotypic studies in Whl/+ and Whl/Whl animals has provided important insights into the pathways that may be affected and thus will facilitate selection of appropriate candidates for further analysis. Our studies indicate that Wheels, a gene which is essential for the survival of the embryo, may link diverse processes involved in vascular, hindbrain and inner ear development. While phenotype-based mutagenesis screens focus on specific physiological, developmental and behavioral phenotypes, isolation and characterization of single-gene mutations with a wide range of phenotypes will be important for a more profound understanding of gene function.

Notes:

Adviser: Maja Bucan.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2001.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3003585.

OCLC:

244971412