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Centre for Trophoblast Research


Folate metabolism and regulation of hematopoiesis during pregnancy


(Supervisor: Dr Erica Watson,


While it is well known that maternal dietary deficiency in folate (also known as folic acid) increases the risk for neural tube defects, other conditions caused by folate deficiency are not as well publicized. For example, the appearance of megaloblastic anemia in folate-deficient humans demonstrates an importance of folate metabolism during erythropoiesis. However, the mechanism is unclear. Normally, folate metabolism is required for DNA synthesis and cellular methylation. Therefore, it is possible that the high rate of proliferation during erythropoiesis might make erythroid progenitors particularly susceptible to impaired DNA synthesis during folate-deficient conditions leading to increased cell death of erythrocyte precursors. There may be an underlying epigenetic defect as well. It is also unclear whether other hematopoietic lineages are affected by folate deficiency. Few models exist to study the effects of abnormal folate metabolism on hematopoiesis since feeding mice less folate does not result in overt hematopoietic defects.


Preliminary data from the Watson lab reveals that mice with a hypomorphic mutation in the Mtrr gene, which is essential for the progression of the folate cycle, results in hematopoietic defects. Remarkably, similar hematopoietic defects arise in wildtype mice if either parent is a carrier for the Mtrr mutation suggesting a parental effect of abnormal folate metabolism. This project will systematically assess the intrinsic, parental and sex-specific effects of the Mtrr mutation on specific haematopoietic lineages to gain a greater understanding of the molecular and epigenetic implications of this metabolic defect on haematopoietic differentiation. The student will also assess the effects of Mtrr deficiency on hematopoiesis during pregnancy and during feto-placenta development in the Mtrrgt model to determine whether the pregnancy-state exacerbates the defects observed and to determine whether there are developmental origins to this disease.


Relevant references:


  1. 1.    Elmore et al (2007) Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab 91(1): 85-97.
  2. 2.    Padmanabhan et al (2013) Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell, 155(1): 81-93.
  3. 3.    Padmanabhan and Watson (2013) Lessons from the one-carbon metabolism: passing it along to the next generation. Repro BioMed Online 27(6): 637-43.