Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance

Abstract

The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.

ATP-dependent chromatin remodeling during mammalian development

“…A NuRD complex containing CHD4 and MBD3 also regulates the differentiation of ESCs, interacting with zinc finger protein of the cerebellum 2 (Zic2) at ESC enhancers (Luo et al, 2015). In agreement with the above findings, CHD proteins are crucial for reprogramming somatic cells to a pluripotent state, and both the NuRD complex and CHD1 improve reprogramming efficiency (Gaspar-Maia et al, 2009;Ozmadenci et al, 2015). Thus, CHD1 and CHD-containing NuRD complexes appear to have roles similar to those of BAF complexes during pre-implantation development and ES cell pluripotency.…”

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

“…Many of these TLR3 activated genes have been implicated in early brain cell fate decisions. Netrin1 is a secreted protein that works in conjunction with its dependence receptor DCC (Deleted in Colorectal Carcinoma) to regulate various pathways involved in axon guidance, apoptosis, neural cell death and cellular reprogramming (Bin et al, 2015; Furne et al, 2008; Ozmadenci et al, 2015). The role of NTN1 has been shown in vivo in floxed and null NTN1 mice.…”

SALL4, the missing link between stem cells, development and cancer

“…Furthermore, SALL4 can interact with the Nucleosome Remodeling and Histone Deacetylation (NuRD) complex 3949 . MBD3, an essential structural component of the NuRD complex, has been shown to be a key regulator in the reprogramming process 50515253 . Though it has been suggested that the SALL4/NuRD interaction may not be required in iPSC reprogramming in a cell fusion model 45 , it remains to be seen whether the same conclusion can be drawn from other approaches in generating iPSCs.…”