Loydie Majewska

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Loydie Majewska, Ph.D.'s photo
Loydie Majewska, Ph.D.
Assistant Professor
Pediatrics and Human Genetics,
McGill University
Mailing address:
Montreal Children's Hospital Research Institute
PT 230,
4060 Ste-Catherine St. West
Montreal, Quebec
H3Z 2Z3
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Research Interests

In my lab we use the mouse as a model system for identifying and characterizing the functions of genes that are required during early development.

Mutations that affect organogenesis or function of the placenta underlie early pregnancy loss and pre-eclampsia, a severe condition that can threaten survival of the fetus and its mother. The placenta, which forms a border between the mother and the developing embryo, is required for exchanges of nutrition, waste, and hormones. In the mouse and in humans, development of the placenta depends on the fusion, or contact, of two extraembryonic membranes: the chorion and the allantois. The genetic cascades regulating the allocation of cells into the chorionic and/or allantoic lineage have been well defined. However, little is understood about the process that regulates critical interactions between these two tissues.

We use the mouse as a model system for normal human development. Presently our research focuses on the cellular and genetic basis of abnormal chorioallantoic attachment in two mouse models: 99J, an n-ethyl-N-nitrosurea (ENU) line identified in a recessive screen for genes regulating mouse development and mice with mutation in the Csk (c-src kinase) locus, which encodes a tyrosine kinase that inhibits integrin signaling. Homozygous mutant Csk or 99J embryos are morphologically indistinguishable from wild type littermates at embryonic day (E) 8.5. However, one day later at E9.5, homozygous mutant embryos are smaller than their normal littermates, and exhibit a number of abnormalities that include: an absence of chorionic fusion, a pointy tail bud, and a failure to undergo chorionic turning. Embryonic death of these mutant embryos between E10.5 and E11.5 is attributed to a failure in placental development as a result of abnormal chorioallantoic. The early death of 99J and Csk homozygous mutant embryos models early pregnancy loss in human. Since, the primary defect in these mouse model is abnormal placentation resulting from a failure of chorioallatnoic attachment, further characterization of the cellular and genetic cascades that regulate chorioallantoic attachment will shed light on early pregnancy loss in human.

Mutations in a number of genes that are required for early pattering of the head and posterior of the mouse embryo have also been shown to be necessary for normal human development. For example, mutations in T, a gene necessary for posterior development, are associated with increased disposition to spina-bifida (OMIM 601397). Mutations in HESX1, a gene that is first expressed in the anterior visceral endoderm, are associated with septooptic dysplasia (OMIM 601802). The availability of Embryonic Stem cells that can be modified in vitro and later used to generate adult mice with specific chromosomal modifications allows us the opportunity to model human diseases in. A lot of emphasis has been placed on the understanding of the anterior and posterior patterning of the embryo. However, relatively little is known about the establishment of the middle streak. Derivatives of the middle streak, which include the paraxial and lateral mesoderm, are essential for normal development and stasis of the adult organism. The paraxial mesoderm contributes to the muscular and skeletal components of the body, while the lateral mesoderm will contribute to the kidneys and the urogenital system. Abnormalities in these derivatives of the middle streak can account for a number of syndromes observed in human, such as Marden-Walker (OMIM 248700) and Walker-Warburg (OMIM 236670) syndromes. The understanding of the signaling pathways and the genetic components involved in middle streak formation will shed light on the etiology of such disorders and help pave the way to their eventual treatment.

Our goal is to identify the genes that are required for pattering the middle streak and its derivatives. Using both candidate gene and non-candidate gene-based approaches.