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Musashi2 protein in homolog 2 in Homo sapiens

The first Musashi (abbreviation Msi) gene was firstly found in the flies’ family Drosophila, although it has been later identified in other eukaryotic species. There are two homologue genes found in mammals, called Musashi 1 (MSI1) and Musashi 2 (Msi2). The last one is expressed as a RNA-binding protein in neuronal progenitor cells, including stem cells, and both normal and leukemic blood cells.[1][2]

Location

Location of the protein

RNA-binding protein Musashi2 appears to be in a wide variety of tissues, such as stem cells, bulge region of the hair follicle, immature pancreatic β-cells and neural progenitor cells.[1] Amongst the last ones, Msi2 is expressed in early stages of development, in the ventricular and subventricular zone,[3] in cells of the astrocyte lineage. It was there when it was first discovered.[1] Within the hematopoietic system, Msi2 is highly expressed in the most primitive progenitors,[1][4] in stem cell compartments,[2] and its overexpression has been found in myeloid leukemia cell lines.[2] In neural cell lines, Msi2 protein, as well as its homologue Msi1, is exclusively located in the Cytoplasm.[3]

Location of the gene

In humans, the codifying gene of Musashi homologue 2 is located in chromosome 17q23.2 [5] and has a sequence length of 1,414bp of with 987bp are encoded.[6] In mouse Msi2 has been found to be in 11qB5-C [3] and BC169841 in Xenopus laevis (African clawed frog).[4]

Structure

There have been identified two different isoforms of Msi2 expressed by embryonic stem cells, isoform 1 and isoform 2. The first one is the larger canonical isoform, and the second one is the shorter, splice-variant Isoform.

Functions

In a crucial way, Musashi 2 is involved in some important processes that enable our organism's development.[7] As the rest of Musashi family RNA-binding proteins, it is linked to tissue stem cells and has an influence in asymmetric cell division, germ and somatic stem cell function and cell fate determination in a variety of tissues.[2]

Apart of being a RNA-binding protein, it is able to act as a translational inhibitor.[4] Because of this property, Musashi2 contributes in more than one vital aspect, as in the development of the nervous system, regulation of the Hematopoietic stem cell (HSC) compartment, or the self-renewal and pluripotency of embryonic stem cells. This molecule takes part in a high number of pathways related to the self-renewal of some stem cells. However, it is not only focused in one specific type. Depending on the tissue where it is located, it develops different functions.

Musashi2 in embryonic stem cells

As it is previously explained, Musashi2 is part of a family of RNA-binding proteins. It belongs to the RNA-processing group of proteins which are associated with the transcription factor SOX2 during the early stages of differentiation. Sox2 is known to be essential during embryogenesis and in the self-renewal and pluripotency of embryonic stem cells. This RNA-binding protein has a high influence on it too, since the gain or loss of self-renewal capacity and the extent of differentiation depends on Msi2 levels. Although both of the isoforms of this protein are needed to the maintenance of the self-renewal, they are different on a functional way and they play different roles in some aspects of the process. For example, only isoform 1 expression is related to the cloning efficiency of embryonic stem cells.[7]

Musashi2 in neural progenitor stem cells

In a similar way to Musashi1, Musashi2 is also active in the proliferation of pluripotent neural precursors cells of the embryo, a process which both Msi1 and Msi2 are strongly co-expressed in. Moreover, these two RNA-binding proteins (Msi1 and Msi2) regulate the multiplication and maintenance of a specific group inside of neural precursors cells: CNS (central neural system) stem cells populations. Therefore, Msi2 plays a significant role in the development and maintenance of CNS stem cells through post-transcriptional gene regulation.[2]

Musashi2 in hematopoiesis

Musashi2 is present in blood too, in which its expression is situated in the hematopoietic system, more commonly in the most primitive cells. These are the LSK cells, which are composed by long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HCSs) and multipotent progenitors (MPPs).[1]

Self-renewal and differentiation processes in hematopoietic stem cells need to be highly regulated in order to maintain homeostasis and to avoid the growing of blood cell malignancies. In this point is where Musashi2 interferes.[4] Therefore, Msi2’s function in HSCs consists on regulating their proliferation and differentiation. Due to this, a decreasing on the level of Msi2 induces a reduction in the number of more primitive progenitors of HSCs.[1]

Functions in pathologies

As Musashi2 is involved in the generation of hematopoietic cells, it is also linked with one of its pathologies:myeloid leukemia. It has been found that Msi2 plays an important role in this kind of leukemia. It is important to consider the two types of this illness: chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML). In both of them, Msi2 regulates hematopoietic steam cells proliferation and does not allow the differentiation of its gene expression.[2]

Chronic myelogenous leukemia

CML progresses from the initial phase, where differentiated myeloid cells are accumulated, to the accelerated phase, where the expansion of these cells increases, and it ends with the blast crisis phase. It has been found that Msi2 participates together with BCR-ABL gene to stimulate the progress to the aggressive phase.[2] The first evidence to consider its role in this phase is its high concentration compared with the first phase of the disease. One of the functions of the Msi2 is to regulate the expression of NUMB, causing its inhibition.[8] Therefore, the function of the Msi2 in this disease is being studied together with Numb expression. However, while Numb is overexpressed during the chronic phase and decreases in the blast one, Musashi starts to be overexpressed in the last fatal phase of CML.[9] The high expression of Msi2 interrupts the cellular differentiation and allows the expansion of immature leukemic cells causing the progress to the deadly phase.[9]

Acute myeloid leukemia

As the AML has a similar behaviour to the aggressive phase of the CML, Msi2’s role is similar as well. It has been found that Msi2 is also overexpressed in this type of leukemia and its activity is related with Numb consequently. Moreover, the high expression of Msi2 is related with a poor clinical outcome.[1] In order to prove this, it has been demonstrated that with Msi’s knockdown leads to a rising apoptosis and differentiation and to a decreasing proliferation.[9] As a result, patients that develop leukemia without a high expression of Msi2 have a better prognostic.

Therapeutic prospects

Some therapeutic prospects are focusing on targeting Numb-Msi2 pathway to predict the accelerated phase of myeloid leukemia. Furthermore, the usage of high concentrations of Msi2 as a biomarker is being studied to help to predict the illness’ development. These investigations are not only increasing scientific knowledge of biochemistry, but also are considerable for improving and creating new medical therapies.[10]

References

  1. ^ a b c d e f g Andrés-Aguayo L, Varas F, Graf T. Musashi 2 in hematopoiesis. Curr Opin Hematol. 2012 Jul; 19(4); 268-72. http://www.ncbi.nlm.nih.gov/pubmed/22517588
  2. ^ a b c d e f g Michael G Kharas, Christopher J Lengner, Fatima Al-Shahrour, Lars Bullinger, Brian Ball, Samir Zaidi, Kelly Morgan, Winnie Tam, Mahnaz Paktinat, Rachel Okabe,Maricel Gozo, William Einhorn, Steven W Lane, Claudia Scholl, Stefan Fröhling, Mark Fleming, Benjamin L Ebert, D Gary Gilliland, Rudolf Jaenisch and George Q Daley. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010 Aug ; 16(8): 903–908. doi:10.1038/nm.2187. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090658/pdf/nihms283893.pdf
  3. ^ a b c Sakakibara S, Nakamura Y, Satoh H, Okano H.RNA-Binding Protein Musashi2: Developmentally Regulated Expression in Neural Precursor Cells and Subpopulations of Neurons in Mammalian CNS. The Journal of Neuroscience, 15 October 2001, 21(20): 8091-8107; http://www.ncbi.nlm.nih.gov/pubmed/11588182
  4. ^ a b c d Andrés-Aguayo L, Varas F, Kallin EM, Infante JF, Wurst W, Floss T, Graf T. Musashi 2 is a regulator of the HSC compartment identified by a retroviral insertion screen and knockout mice. Blood. 2011 Jul 21; 118(3); 554-64 http://www.ncbi.nlm.nih.gov/pubmed/21613258
  5. ^ http://www.genenames.org/data/hgnc_data.php?hgnc_id=18585
  6. ^ http://www.ebi.ac.uk/ena/data/view/AAH01526
  7. ^ a b Wuebben E. L., Mallana S. K., Cox J.L., Rizzino A. Musashi2 Is Required for the Self-Renewal and Pluripotency of Embryonic Stem Cells. PLoS ONE 7(4):e34827. doi:10.1371/journal.pone.00348272012 Apr; http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034827
  8. ^ Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010; 466:765-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/
  9. ^ a b c Griner LN, Reuther GW. Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway. Cancer Biology & Therapy 10:10, 979-982; November 15, 2010; © 2010 Landes Bioscience http://www.landesbioscience.com/journals/cbt/03GrinerCBT10-10.pdf
  10. ^ Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7:441-53. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107545/
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