Developmental Expression of Musashi-1 and Musashi-2 RNA-Binding Proteins During Spermatogenesis: Analysis of the Deleterious Effects of Dysregulated Expression1

Abstract

Spermatogenesis is a complex developmental process whereby diploid spermatogenic stem cells become haploid and undergo a series of morphological changes to produce physically mature spermatozoa. Crucial to this process are a number of RNA-binding proteins, responsible for the posttranscriptional control of essential mRNAs and particularly pertinent to the two periods of inactive transcription that occur in spermatogenesis. One such group of RNA-binding proteins is the Musashi family, specifically Musashi-1 (MSI1) and Musashi-2 (MSI2), which act as key translational regulators in various stem cell populations and have been linked with the induction of tumorigenesis. In the present study, we examined the differential expression of mammalian MSI1 and MSI2 during germ cell development in the mouse testis. MSI1 was found to be predominately localized in mitotic gonocytes and spermatogonia, whereas MSI2 was detected in meiotic spermatocytes and differentiating spermatids. Extensive examination of the function of Musashi in spermatogenesis was achieved through the use of two transgenic mouse models with germ cell-specific overexpression of full-length isoforms of Msi1 or Msi2. These models demonstrated that aberrant expression of either Msi1 or Msi2 has deleterious effects on normal spermatogenesis, with Msi2 overexpression resulting in male sterility. Studies undertaken on human testicular seminoma tumors provide further insights into the relevance of MSI1 and MSI2 overexpression as diagnostic markers to human stem cell cancers. Overall this study provides further evidence for the unique functions that RNA-binding protein isoforms occupy within spermatogenesis, and introduces the potential manipulation of the Musashi family proteins to elucidate the mechanisms of posttranscriptional gene expression during germ cell development.

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

“…This was followed by additional studies showing roles for the Musashi proteins in regulating normal cell differentiation and organ development for other tissue types (5,11–15), emphasizing the essential nature of this protein signaling over great evolutionary distance. For example, in early studies in mice, Msi1 was found to be highly expressed in the brain, and Msi1 deficiency caused hydrocephaly (16).…”

Musashi-2 promotes migration and invasion in bladder cancer via activation of the JAK2/STAT3 pathway

“…9 More recent studies showed that Msi2 may have a unique role that is required for normal spermatogenesis, with Msi2 overexpression resulting in male sterility in vivo. 10 Apart from being a cell development regulator, Msi2 is also linked to carcinogenesis and tumor progression. Recent studies have shown that Msi2 is a mediator of proliferation and differentiation in myeloid malignancies, 9 and its knockdown leads to cell cycle arrest and cell apoptosis in acute myeloid leukemia (AML).…”

Interplay between the RNA binding‐protein Musashi and developmental signaling pathways

“…Both have two RNA-recognition motifs, das Chagas and Baroni contributed equally to this work. [15][16][17][18][19] In germ cells, however, both, can influence translational modulation during the differentiation and maintenance of maturation of these cells [20][21][22] and any dysregulation can lead to cellular dysfunctions promoting tissue instability, as well as the onset of tumor progression. The RRM1 of MSI1 protein contains 20-110 amino acid residues and RRM2 contains amino acid residues.…”