This report describes use of Drosophila neural stem cells to investigate the processes that normally prevent dedifferentiation. Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state. This process may be implicated in the development of cancer in general and has been proposed, specifically, to contribute to development of glioblastoma.
Notch (N) signaling is central to the self-renewal of neural stem cells (and stem cells of other tissues); Notch hyperactivation in neural stem cells results in dedifferentiation. A number of genes that play a role in this process have been identified, including eukaryotic translation initiation factor 4E (eIF4E1), the transcription factor lola, and the microRNA mir-ban. See also the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).
The zinc finger transcription factor nerfin-1 has been characterized extensively in the context of this cancer model. nerfin-1 is expressed in post-mitotic larval neurons and is necessary to maintain their differentiated status. There are two genes orthologous to nerfin-1 in human, the transcriptional regulators INSM1 and INSM2; INSM1 is known to play a key role in neurogenesis and neuroendocrine cell differentiation during embryonic and fetal development. There is a second related gene in Drosophila, nerfin-2. Neither human gene, INSM1 or INSM2, has been introduced into flies.
In order to assess loss-of-function phenotypes of nerfin-1, somatic clones were generated in the larval CNS. In the absence of nerfin-1, neurons dedifferentiate, rapidly increase in size, undergo reversion to acquire a neuroblast cell fate, and become highly proliferative. Clones continue to be highly proliferative during adult stages, producing neural tumors and resulting in a reduced lifespan; these tumors were capable of metastasis when transplanted into the abdomen of naive adult hosts, migrating to distant organs such as the eye. Ectopic expression of nerfin-1 promotes premature differentiation and neuroblast loss. The work in this system primarily addresses the dedifferentiation of type I neural stem cells.
In Drosophila, multiple genes have been found to impact dedifferentiation of type II neural stem cells, including components of the integrator complex. Several recently described neurodevelopmental diseases in human are associated with genes of the integrator complex (see FBhh0001140).
[updated Nov. 2019 by FlyBase; FBrf0222196]
In a mouse model of glioblastoma, it was observed that differentiated cells in the CNS appear to undergo dedifferentiation to generate a neural stem cell or progenitor state to initiate and maintain the tumor progression (Friedmann-Morvinski et al., 2012; pubmed:23087000).
INSM1 encodes a sequence-specific DNA-binding transcriptional regulator that plays a key role in neurogenesis and neuroendocrine cell differentiation during embryonic and/or fetal development. [Gene Cards, INSM1; 2019.11.07]
High-scoring ortholog of human EIF4E and EIF4E1B (multiple related genes in both species). Dmel\eIF4E1 shares 40-42% identity and 51-62% similarity with the human genes.
Moderate- to high-scoring ortholog of human INSM1 and INSM2 (2 Drosophila to 2 human). Dmel\nerfin-1 shares 27% identity and 36-37% similarity with the human genes.
Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.
Low-scoring ortholog of human ZBTB20; many related genes in both species.
5' seed sequence homologous to that of human MIR450B-3p (FBrf0242402).