Musashi-2
Musashi-2, also known as Musashi RNA binding protein 2, is a protein that in humans is encoded by the MSI2 gene. Like its homologue musashi-1, it is an RNA-binding protein involved in stemness.
Expression
There are two homologue genes found in mammals, called musashi1 and musashi-2. Musashi-2 is an RNA-binding protein expressed in neuronal progenitor cells, including stem cells, and both normal and leukemic blood cells.Musashi-2 also appears to be expressed in stem cells and in a wide variety of tissues, including the bulge region of the hair follicle, immature pancreatic β-cells and neural progenitor cells. Amongst the last ones, MSI2 is expressed in early stages of development, in the ventricular and subventricular zone, in cells of the astrocyte lineage. It was there that it was first discovered. Within the hematopoietic system, MSI2 is highly expressed in the most primitive progenitors, in stem cell compartments, and its overexpression has been found in myeloid leukemia cell lines. In neural cell lines, MSI2 protein, as well as its homologue MSI1, is exclusively located in the cytoplasm.
In humans, the MSI2 gene is located in chromosome 17q23.2. and has a sequence length of 1,414bp of which 987bp are encoded. In mice, MSI2 has been found to be in 11qB5-C and BC169841 in the African clawed frog. There are two different isoforms of MSI2 expressed by embryonic stem cells that result from alternative splicing, isoform 1 and isoform 2. The first one is the larger canonical isoform, and the second one is the shorter, splice-variant Isoform.
Function
This gene encodes an RNA-binding protein that is a member of the Musashi protein family. The encoded protein is translational regulator that targets genes involved in development and cell cycle regulation. Mutations in this gene are associated with poor prognosis in certain types of cancers. This gene has also been shown to be rearranged in certain cancer cells. The first musashi gene was first discovered in Drosophila and then later identified in other eukaryotic species.MSI2 is involved in organismal development. As with the rest of Musashi family RNA-binding proteins, MSI2 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.
As an RNA-binding protein, MSI2 is acts as a translational inhibitor. Through this molecular mechanism, MSI2 contributes in more than one vital aspect, as in the development of the nervous system, regulation of the Hematopoietic stem cell compartment, or the self-renewal and pluripotency of embryonic stem cells. MSI2 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.
Embryonic stem cells
MSI2 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. MSI2 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.Neural progenitor stem cells
In a similar way to MSI1, MSI2 is also active in the proliferation of pluripotent neural precursors cells of the embryo, during which both MSI1 and MSI2 are strongly co-expressed. Moreover, MSI1 and MSI2 regulate the multiplication and maintenance of a specific group inside of neural precursors cells: CNS stem cells populations. Therefore, MSI2 plays a significant role in the development and maintenance of CNS stem cells through post-transcriptional gene regulation.Hematopoiesis
MSI2 is present in blood cells, 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, short-term HSCs and multipotent progenitors.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. It is this point is where Musashi-2 interferes. Therefore, MSI2's function in HSCs consists of regulating their proliferation and differentiation. Therefore, a decreasing on the level of MSI2 induces a reduction in the number of more primitive progenitors of HSCs.