PiN Faculty Member - Mary Loeken, PhD

Mary Loeken, PhD

Associate Professor of Medicine (Physiology)

Joslin Diabetes Center
Research Division
One Joslin Pl.
Boston, MA 2215
Tel: 617 309-2525
Fax: 617 309-2650
Email: mary.loeken@joslin.harvard.edu
Visit my lab page here.



The neural tube forms the scaffolding upon which the central nervous system forms. Therefore, proper formation of the neural tube is essential for successful development of the brain and spinal cord. Diabetic pregnancy significantly increases the risk for congenital malformations, especially neural tube defects. The Loeken lab seeks to understand the molecular regulation of early neural tube formation, and to understand the mechanisms by which diabetic pregnancy causes neural tube defects. We have shown that excess glucose transported to the embryo during maternal hyperglycemia disturbs the balance of aerobic and anaerobic metabolism that is crucial in the control of cell proliferation and differentiation. This causes hypoxic and oxidative stress, which activates the AMP kinase signaling pathway, which leads to deficient expression of genes in the embryo that control developmental programs. In particular, expression of Pax3, a gene that is essential for neural tube closure, is significantly impaired. We recently showed that oxidative stress stimulates activity of a DNA methyltransferase, Dnmt3b, preventing the hypomethylation of a Pax3 CpG island that normally occurs during differentiation, thereby suppressing the onset of Pax3 expression. Using a variety of molecular and genetic approaches, we have shown that Pax3 stimulates degradation of the p53 tumor suppressor protein during neural tube development, and that neural tube defects in Pax-3deficient embryos results from derepression of p53-dependent apoptosis. Current experiments are performed using a combination of mouse strains, as well as embryonic stem cells that can be induced to differentiate to neuronal precursors. We are investigating how Pax3 chromatin is regulated during differentiation and during oxidative stress and the mechanism by which Pax3 stimulates p53 degradation.



Last Update: 12/5/2014



Publications

For a complete listing of publications click here.

 


 



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