Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells

Abstract

We and others showed previously that PR domain-containing 16 (Prdm16) is a transcriptional regulator required for stem cell function in multiple fetal and neonatal tissues, including the nervous system. However, Prdm16 germline knockout mice died neonatally, preventing us from testing whether Prdm16 is also required for adult stem cell function. Here we demonstrate that Prdm16 is required for neural stem cell maintenance and neurogenesis in the adult lateral ventricle subventricular zone and dentate gyrus. We also discovered that Prdm16 is required for the formation of ciliated ependymal cells in the lateral ventricle. Conditional Prdm16 deletion during fetal development using Nestin-Cre prevented the formation of ependymal cells, disrupting cerebrospinal fluid flow and causing hydrocephalus. Postnatal Prdm16 deletion using Nestin-CreER T2 did not cause hydrocephalus or prevent the formation of ciliated ependymal cells but caused defects in their differentiation. Prdm16 was required in neural stem/ progenitor cells for the expression of Foxj1, a transcription factor that promotes ependymal cell differentiation. These studies show that Prdm16 is required for adult neural stem cell maintenance and neurogenesis as well as the formation of ependymal cells.

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

“…Ham is the fly homolog of Prdm16 in vertebrates, and has been shown to play a key role in regulating cell fate decisions in multiple stem cell lineages (Baizabal et al, 2018;Harms et al, 2015;Moore et al, 2002;Shimada et al, 2017). Prdm16 contains two separately defined zinc finger motifs, each of which likely recognizes unique target genes.…”

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

“…PRDM16 is expressed in radial glia in all telencephalic proliferative zones, suggesting that it might play a key role in the specification of most forebrain neuron lineages (Baizabal et al, 2018;Chuikov et al, 2010;Inoue et al, 2017;Shimada et al, 2017). It is unclear whether Prdm16 regulates the same progenitor cell behaviors and transcriptional programs in dorsal and ventral progenitors.…”

“…In order to understand how the balance of excitation and inhibition is achieved in the developing cortex, it is necessary to know the mechanisms by which MGE progenitors regulate their proliferation and consequently their neuronal output (Lim et al, 2018;Petryniak et al, 2007). One critical factor that ensures correct neural progenitor amplification and cell lineage progression is PRDM16, a transcriptional regulator that is specifically expressed in radial glia of the developing telencephalon (Baizabal et al, 2018;Chuikov et al, 2010;Shimada et al, 2017). In the cortex, Prdm16 controls indirect neurogenic divisions, radial glia lineage progression and the production of late born upper layer pyramidal neurons by regulating the epigenetic state of developmental enhancers (Baizabal et al, 2018).…”

Brain ependymocytes in neurogenesis and maintaining integrity of blood-cerebrospinal fluid barrier

“…Недавно была представлена информация о механизмах развития гидроцефалии при нарушении функционирования реснитчатого аппарата эпендимальных клеток. В частности, показана роль регулятора транскрипции PRDM16, который обеспечивает дифференцировку нейральных стволовых клеток в ресничные эпендимальные клетки в пределах нейрогенных ниш [13]. Авторами убедительно доказано, что изменения PRDM16 во время внутриутробного развития у грызунов приводят к нарушению образования эпендимальных клеток, нарушениям движения ликвора и, в итоге, к гидроцефалии.…”