Control of the Normal and Pathological Development of Neural Stem and Progenitor Cells by the PC3/Tis21/Btg2 and Btg1 Genes

Abstract

The PC3/Tis21/Btg2 and Btg1 genes are transcriptional cofactors belonging to the Btg/Tob family, which regulate the development of several cell types, including neural precursors. We summarize here the actions of these genes on neural precursors in the adult neurogenic niches and the cognitive defects associated when their expression is altered. We consider also recent findings implicating them in neural and non-neural tumors, since common developmental mechanisms are involved. PC3/Tis21 is required for the regulation of the maturation of stem and progenitor cells in the adult dentate gyrus and subventricular zone (SVZ), by controlling both their exit from the cell cycle and the ensuing terminal differentiation. Such actions are effected by regulating the expression of several genes, including cyclin D1, BMP4, Id3. In cerebellar precursors, however, PC3/Tis21 regulates chiefly their migration rather than proliferation or differentiation, with important implications for the onset of medulloblastoma, the cerebellar tumor. In fact PC3/Tis21 is a medulloblastoma-suppressor, as its overexpression in cerebellar precursors inhibits this tumor; PC3/Tis21 shows anti-tumor activity also in non-neural tumors. Btg1 presents a different functional profile, as it controls proliferation in adult stem/progenitor cells of dentate gyrus and SVZ, where is required to maintain their self-renewal and quiescence, but is apparently devoid of a direct control of their terminal differentiation or migration. Notably, physical exercise in Btg1-null mice rescues the loss of proliferative capability occurring in older stem cells. Both genes could be further investigated as therapeutical targets, namely, Btg1 in the process of aging and PC3/Tis21 as a tumor-suppressor.

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

“…As a whole, these data may suggest the possibility that the ablation of Tis21 , by altering the expression of important Shh marker genes such Pdgfd and Gli1 , may increase the penetrance of the Shh-type tumor phenotype, but also the possibility of a shift of the Shh phenotype toward the group 3 MB. A possible shift toward group 3, associated with retinal development control, may underlie the intriguing novel concept that the inactivation of a gene—in this case Tis21 , which is known to be required for the terminal differentiation of neural stem cells (Micheli et al, 2015)—may favor in Shh-activated GCPs a lineage shift toward other neural cell types involved in group 3 MB onset. Further analyses will be necessary to clarify this possibility.…”

Post‐transcriptional regulation of gene expression in neural stem cells

“…Amongst the BTG/TOB protein family, the PC3/Tis21/Btg2 and Btg1 genes have been known to regulate the maturation of NSPCs in the adult dentate gyrus and SVZ. Interestingly, whilst Btg2 induces the terminal differentiation of NSPCs, Btg1 seems not to be involved in stem cell terminal differentiation …”

“…Interestingly, whilst Btg2 induces the terminal differentiation of NSPCs, Btg1 seems not to be involved in stem cell terminal differentiation. 38 Nonsense-mediated mRNA decay is a specific type of post-transcriptional regulatory mechanism for mRNA quality control. As a surveillance system existing in eukaryotes, NMD is linked to pre-mRNA splicing and mRNA translation.…”

Minireview: Syndecans and their crucial roles during tissue regeneration

“…There are various type of progenitor cells in mammalian tissues including skin (epidermal stem cells) [83], blood vessel (vascular progenitor cells) [84], bone (bone marrow) [85], skeletal muscle (satellite cells) [86], and nerve (neural stem cells) [87], and they are involved in sustaining tissues by selfrenewal. There are various type of progenitor cells in mammalian tissues including skin (epidermal stem cells) [83], blood vessel (vascular progenitor cells) [84], bone (bone marrow) [85], skeletal muscle (satellite cells) [86], and nerve (neural stem cells) [87], and they are involved in sustaining tissues by selfrenewal.…”

“…During tissue regeneration, the recruitment of adult stem cells or progenitor cells is an important component, as in development. There are various type of progenitor cells in mammalian tissues including skin (epidermal stem cells) [83], blood vessel (vascular progenitor cells) [84], bone (bone marrow) [85], skeletal muscle (satellite cells) [86], and nerve (neural stem cells) [87], and they are involved in sustaining tissues by selfrenewal. In invertebrates, Drosophila also has adult stem cells in its intestine and ovary [88,89].…”