Zac1 Regulates Astroglial Differentiation of Neural Stem Cells Through Socs31. (23rd August 2013)

• Record Type: Journal Article
• Authors: Schmidt‐Edelkraut, Udo; Hoffmann, Anke; Daniel, Guillaume; Spengler, Dietmar
• Is Part Of: Stem cells. Volume 31:Number 8(2013:Aug.)
• Page Start: 1621
• Page End: 1632
• Publication Date: 2013-08-23
• Subjects: Astrocytes -- Differentiation -- Neural stem cell -- Zac1 -- Socs3 -- Imprinting; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1405
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Cell‐fate decisions and differentiation of embryonic and adult neural stem cells (NSC) are tightly controlled by lineage‐restricted and temporal factors that interact with cell‐intrinsic programs and extracellular signals through multiple regulatory loops. Imprinted genes are important players in neurodevelopment and mental health although their molecular and cellular functions remain poorly understood. Here, we show that the paternally expressed transcriptional regulator Zac1 (zinc finger protein regulating apoptosis and cell cycle arrest) is transiently induced during astroglial and neuronal differentiation of embryonic and adult NSC lines. Thereby, Zac1 transactivates Socs3 (suppressor of cytokine signaling 3), a potent inhibitor of prodifferentiative Jak/Stat3 signaling, in a lineage‐specific manner to prevent precocious astroglial differentiation. In vivo, Zac1 and Socs3 colocalize in the neocortical ventricular zone during incipient astrogliogenesis. Zac1 overexpression in primary NSCs delays astroglial differentiation whereas knockdown of Zac1 or Socs3 facilitates formation of astroglial cells. This negative feedback loop is unrelated to Zac1′s cell cycle arrest function and specific to the Jak/Stat3 pathway. Hence, reinstating Jak/Stat3 signaling in the presence of increased Zac1 expression allows for timely astroglial differentiation. Overall, we suggest that the imprinted gene Zac1 curtails astroglial differentiation of NSCs in the developing and adult brain. STEM Cells 2013;31:1621–1632