Aimee K. Ryan
- Aimee K. Ryan, Ph.D.
- Assistant Professor
Pediatrics and Human Genetics,
McGill University - Mailing address:
- Montreal Children's Hospital Research Institute
PT 415-2,
4060 Ste-Catherine St. West
Montreal, Quebec
H3Z 2Z3 - Email:
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- Biosketch:
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Research Overview
The goal of our research program is to investigate the molecular and morphological events that underlie the normal development of vertebrate embryos. Our lab focuses on molecules that participate in the establishment and formation of the left-right axis and understanding how they affect asymmetric morphogenesis. Proper formation of the left-right axis is essential to direct subsequent asymmetric development and positioning of the internal organs to permit their efficient packing within the vertebrate body cavity. The organization of internal organs is conserved and variations from the normal pattern disrupt physiological function and often leading to life threatening complications.
As with all embryonic patterning events, asymmetric morphogenesis requires the conversion of extra-cellular signals into changes in intracellular gene expression that lead to cell/tissue remodeling, migration and differentiation. Although several molecules have been placed into a left-right signaling cascade, many are still unknown, and precisely how they direct the morphogenetic mechanisms remain obscure.
Research Interests
How does Pitx2c direct left-right patterning? As a postdoctoral fellow, I collaborated with Juan Carlos Izpisúa Belmonte’s group to show that Pitx2 has an evolutionarily conserved role in patterning the left-right axis. It remains the most downstream component of the pathway that directs asymmetric organ development. Pitx2c is asymmetrically expressed on the left side of the lateral plate mesoderm, which plays a critical role in patterning asymmetric morphogenesis. It is also expressed on the left side of several organs that become asymmetrically positioned with respect to the midline. Pitx2c is a member of the bicoid-related family of homeodomain transcription factors. However, no gene targets have been identified with respect to its role in left-right patterning. Currently, we are characterizing the molecular mechanisms employed by Pitx2c to exert its left-right patterning function.
What is the role of tight junctions in left-right patterning? A second goal of our lab is to identify new molecules required for establishing the left-right axis, examine their role in asymmetric morphogenesis and ultimately determine how mutations in these genes contribute to laterality defects and congenital anomalies in humans. We performed a subtractive screen for factors that are differentially expressed on the left and right sides of bilaterally symmetrical chick embryo. One of the molecules that we identified in this process was the tight junction protein, Claudin-1. Tight junctions are critical for maintaining cell polarity and determining how cell layers interact since they regulate the paracellular transport of small molecules between cell layers. We showed that over-expression of Claudin-1 on the right side of the embryo randomized the direction of heart looping, the first gross morphological sign of left-right asymmetry. This activity was dependent on an intact protein kinase C recognition site in Claudin-1’s cytoplasmic tail. We are now investigating the role of endogenous Claudin-1 and its interactions with other proteins at the tight junction cytoplasmic plaque in this process.