Joslin Investigator Details

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	Joslin Investigator:

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CV not available

Member of Section:

Current Fellows, Students, or Lab Members:

James Chappell, Ph. D.

Zaheer Sameermahmood, Ph.D.

Xiaodan Wang, Ph.D.

Sheller Zabihi, Ph.D.

Yong Zhang, PhD

Past Fellows, etc.:

Jin Cai

Michael Curley, Ph.D.

Claudia Eberle, MD

April Hill

Matthew Lann

Hyung-Yul Lee, MD

Rulin Li

Sarah Morgan, Ph.D.

Lydie Pani

Shelley Phelan

Foteini Stamatelou

Shoba Thirumangalathu

Marta Viana, PhD

Fangnian Wang

Yichao Wu

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Adjunct Investigators

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Mary R Loeken, PhD

Investigator

Joslin Diabetes Center

1/5/1988 -

Diabetes and Pregnancy

Maternal diabetes increases the risk for congenital malformations, however, until recently, it has not been well understood how they occur. My laboratory showed that diabetic pregnancy-induced congenital malformations are caused by inhibiting expression of genes which control essential developmental processes. In recent years, we have elucidated many of the biochemical pathways by which the diabetic environment interferes with the normal expression of embryo genes, and how disrupted gene expression causes congenital malformations.

We have focused on the neural tube, one of the major structures that can be malformed in diabetic pregnancies. Using a mouse model of diabetic pregnancy that we developed, we have shown that expression of Pax3, a gene encoding a transcription factor required for neural tube and neural crest development, is significantly reduced in embryos of diabetic mice. Because there are no redundant pathways to compensate for Pax3 deficiency, reduced expression of Pax3 below a critical threshold at essential stages of development is sufficient to induce a neural tube defect. The inhibition of Pax3 results from increased glucose delivery to the embryo from maternal circulation and increased glucose metabolism by the embryo. Through a complex network of biochemical processes involving excess glycolytic and hexosamine flux and increased oxidative metabolism, oxidative stress occurs. Surprisingly, the oxidative stress results, in part, from increased oxygen consumption by the embryo, leading to hypoxic stress. The increased oxidant status of the embryo interferes with the ability of transcription factors to regulate specific sequences of the Pax3 gene promoter. Our research could have a major impact on the understanding of general mechanisms by which neural tube defects occur, as many agents, such as anticonvulsant drugs and folic acid deficiency, which also induce neural tube defects, induce oxidative stress. We also showed that neural tube defects resulting from Pax3 deficiency are caused by de-repression of p53-dependent apoptosis. Interestingly, this could explain the pathogenesis of some human cancers such as melanoma, rhabdomyosarcoma, and neuroblastoma in which PAX3 is inappropriately expressed. We found that susceptibility or resistance to the effects of maternal diabetes on Pax3 expression and neural tube defects is genetically determined. Identification of the susceptibility gene(s) may assist in delineating biochemical pathways by which Pax3 is regulated, and may make it possible to screen for increased risk for neural tube defects in humans.

In addition to the pregnant diabetic mouse model, we employ mouse embryonic stem cell lines. ES cells can be grown in large quantities and can be induced to differentiate into Pax3-expressing neuronal precursors, making it possible to perform many molecular and proteomic procedures which are not possible using embryos. This research has been performed using already-established ES cell lines, and some that have been established in our laboratory. In the course of establishing our own lines, we demonstrated that the efficiency of establishing new ES cell lines can be significantly improved by isolating the lines in glucose and oxygen concentrations that approximate those of the intrauterine environment.

The current work of the Loeken laboratory is focusing on the following questions: What are the transcription factors and transcriptional processes that are induced during neuroepithelial/neural crest development? How does oxidative stress interfere with expression or modification of transcription factors which regulate Pax3? How does Pax3 inhibit p53 synthesis or stability? What is the importance of the regulation of p53 by Pax3 during patterning and cell fate determination?

Biographical Sketch:

Mary Loeken, Ph.D., is an Investigator in the Section on Developmental and Stem Cell Biology at Joslin and an Associate Professor of Medicine at Harvard Medical School. She received her doctorate in Reproductive Endocrinology at the University of Maryland School of Medicine and did postdoctoral training at the National Cancer Institute's Laboratory of Molecular Virology before coming to Joslin. In 1992 she was named a Capps Scholar in Diabetes Research at Harvard Medical School, which also awarded her a Scholars in Medicine Award in 1998. She is an expert on the study of birth defects resulting from diabetic pregnancy and has served on study sections for the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, and on the Editorial Board for the journal, Diabetes.

Selected Publications:

Pani, L, Horal, M, Loeken, MR. Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: Implications for Pax-3-dependent development and tumorigenesis. Genes and Development, 2002; 16, 676-680.

Chang, TI, Horal, M, Jain, SK, Wang, F, Patel, R, Loeken, MR. Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia, 2003; 46, 538-545.

Horal, M, Zhang, A, Stanton, R., Virkamaki, A, Loeken, MR. Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: Involvement in diabetic teratogenesis. Birth Defects Research Part A: Clinical and Molecular Teratology, 2004; 70: 519-527.

Li, R, Chase, M, Jung SK, Smith PJ, Loeken, MR Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Encrinol Metab, 2005; 289:E591-599. E-Pub May 31, 2005.

Wang, F, Thirumangalathu, S, Loeken, MR Establishment of new mouse embryonic stem cell lines is improved by physiological glucose and oxygen. Cloning and Stem Cells, 2006; 8(2):108-16.