REST Regulates Non–Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II

Abstract

RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non-cellautonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non-cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non-cell-autonomously via SCG2.

Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation

“…Notably, REST is involved in neurite outgrowth in differentiated neuroblastoma cell line and primary neurons34. On the other hand, the role of TRIM28 in neurite outgrowth is unclear although several evidences have suggested a potential link between TRIM28 and embryonic development9.…”

“…Though only one previously identified interacting partner was included in our intractome due to the limited number of known REST-interacting proteins, it is statistically significant. The reason why well-established interacting proteins such as Sin3A, HDAC13940 and HDAC234 were not detected in our analysis can be due to the fact that AP-MS could depend on the expression levels of proteins in host cell which we used to make cell lysate. Although CoREST, mSin3 and HDAC1/2 were expressed in HEK293T cell based on microarray data of HEK293T cell (One of ENCODE transcriptome data41; GEO accession: GSE1580542), their expression was not that high.…”

Serum levels of chromogranins and secretogranins correlate with the progress and severity of Parkinson's disease

“…Granins are the major proteins in the core of secretory granules, where they may account for up to 80% of the total core proteins. Cgs and Sgs are involved in gastrointestinal endocrine tumors, neuroendocrine tumors, metabolic disease, and cardiovascular disease . Currently, it is not known whether the granin family plays a role in neurodegenerative diseases such as PD.…”

“…Cgs and Sgs are involved in gastrointestinal endocrine tumors, neuroendocrine tumors, metabolic disease, and cardiovascular disease. [19][20][21] Currently, it is not known whether the granin family plays a role in neurodegenerative diseases such as PD. Here, we investigated the correlation between serum levels of three granins (CgA, CgB, and SgII) and PD severity.…”

Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience

“…It will be interesting to explore combinatorial approaches in which lineage-specific transcription factors and small molecules or morphogens are applied in a timed, concerted manner. However, it is possible that extended maturation times might be required to generate truly mature neurons, and accelerated maturation might lead to cells stuck in a functionally premature state 33,35,155 .…”