Graduate Research Prize Winners 2010
Towards the end of my baccalaureate, I was undecided between pursuing a degree in Art or Biology. I finally went for a Foundation course in Art and Design at Chelsea College London. Having realised, during that year of Foundation course, that I still really wanted to study Biology, I then attended a BSc in Biology at Imperial College London. It was only during the last year of my BSc that I seriously considered the possibility of pursuing a career in academic research and decided to attend the MSc in Integrated Immunology, here in Oxford. During the MSc year, I found the enthusiasm and research topic of one of the lecturers particularly inspiring. When I found out that a PhD position was available to join that lecturer's lab, I immediately applied. In October 2006, I started my DPhil in Dr Katja Simon's lab, entitled: "The role of autophagy in the immune system in vivo".
Figure legend: Atg7-/- erythroid cells accumulate damaged mitochondria. Representative electron micrographs of wild type (left) and conditional Atg7 knockout mice in the haematopoietic system (Vav-Atg7-/-; right) peripheral RBCs (Scale bars: 1 μm). Taken by Prof. D. J. P. Ferguson (NDCLS).
Autophagy is a regulated lysosomal degradation pathway that takes place in the cytoplasm of eukaryotic cells and involves the formation of a double-membraned vesicle, the autophagosome, which sequesters cytoplasmic cargo and delivers it to the lysosomes for degradation. As autophagy gene knockout mice are neonatally lethal, we used a conditional knockout approach to obtain mice lacking the essential autophagy gene Atg7 in the haematopoietic system only. This led to the discovery that deleting autophagy in the haematopoietic system causes lethality of mice at a median age of 12 weeks, with a very severe anaemia as their most striking symptom. This finding precluded the study of the immune system in this model, and shifted the focus of my PhD to the understanding of the role of autophagy in haematopoiesis, and in particular, erythropoiesis.
Mammalian red blood cells (RBCs) are anucleated and devoid of organelles. While their nucleus was known to be expulsed during development, how developing RBCs get rid of their organelles was not well understood. Autophagy being responsible for the clearance of old or damaged organelles in cells, we hypothesized it could play a role in organelle removal during erythrocyte development. Indeed, we found that autophagy is essential for the selective removal of mitochondria from maturing RBCs. In its absence erythrocyte development is therefore impaired, which explains, at least in part, the severe anaemia observed in our model. More recently, we have also found that Atg7 is essential for the maintenance of haematopoietic stem cells and the prevention of leukaemia. Overall, this project has highlighted essential roles for autophagy in haematopoietic cells and suggests that reduced autophagy levels may be the basis for some human anaemias or leukaemias.
The NDM, University of Oxford, was a great platform to start my scientific career; I am now hoping to continue investigating the haematopoietic system at a postdoctoral level.
- Mitochondrial clearance by autophagy in developing erythrocytes: Clearly important, but just how much so? Mortensen M, Ferguson DJ, Simon AK. Cell Cycle. 2010 May 23;9(10).
- Nonredundant role of Atg7 in mitochondrial clearance during erythroid development. Mortensen M, Simon AK. Autophagy. 2010 Apr;6(3):423-5.
- Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Mortensen M, Ferguson DJ, Edelmann M, Kessler B, Morten KJ, Komatsu M, Simon AK. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):832-7.