Advancing Epigenetics Towards Systems Biology

From Dicer-mice to men

1508

Dicer was given its name by Emily Bernstein, a graduate student in Greg Hannon's group at the Cold Spring Harbor Laboratory, who first demonstrated the enzyme's dsRNA "dicing" activity

April 2010

Stefan Janusz reports on how research on mice may shed new light on the development of cancerous tissue

If the pancreas cannot function properly, our ability to digest and absorb fat - an essential component of cell structure - poses a fundamental threat to our wellbeing. After cystic fibrosis, the second most common cause of exocrine pancreatic insufficiency in children is a disorder called Schwachman-Bodian-Diamond (SBD) syndrome; a precondition for leukaemia. Characterised by bone marrow dysfunction, the underlying causes of the syndrome, first documented in the 1960s, are still not well understood.

David Scadden - in collaboration with Matthias Merkenschlager of the MRC Clinical Sciences Centre (Lymphocyte Development Group) - and his team at Massachussetts General Hospital and Harvard Medical School have reported findings that may go some way to uncovering the abnormal developmental mechanisms that lead to the syndrome. They crossed mice lacking the gene Dicer – which is important in the biogenesis of microRNAs – with another strain expressing a tagged protein under the transcriptional control of of a promoter ('osterix') found in osteoblasts.

Osteoblasts in bone marrow provide the tissue-specific niches for haematopoietic stem cells, which are the progenitors of all the cells constituent in blood. The mouse strain resulting from the cross-breeding carried out in the study was deficient in Dicer specifically in osteoblast progenitors and their progeny, including osteoblast precursors and mature osteoblasts. While the specificity of the osterix promoter was such that Dicer was expressed normally in haematopoietic stem cell, bone marrow dysfunction – or myelodysplasia – was observed in addition to a reduction in white blood cells. Some of the mice eventually developed secondary leukaemias.

This phenotype is highly reminiscent Shwachmann-Bodian-Diamond syndrome. Deletion of the gene mutated in the syndrome, Sbds, in osteoprogenitor cells recreated the haematopoietic phenotype in the Dicer-deficient mice.

Although precisely which microRNAs in osteoblasts are crucial for haematopoiesis requires further investigation, the study has demonstrated that abnormalities in stromal cells like osteoblasts can result in tumourigenesis in other cells.

Read the original research article

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