A Common Embryonic Origin of Stem Cells Drives Developmental and Adult Neurogenesis

Abstract

Graphical AbstractHighlights d The Hopx-CreER T2 line can label an embryonic origin of adult dentate neural progenitors d Hopx + dentate progenitors exhibit constant lineage specification across development d Developmental and adult dentate neurogenesis are one continuous process d Hopx + dentate progenitors retain common molecular signatures across development SUMMARY New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx + precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx + neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx + quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx + embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a ''continuous'' model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.

Regulation of active and quiescent somatic stem cells by Notch signaling

“…Immature neurons migrate outside of the VZ into outer layers of the brain, where they become mature neurons, while intermediate progenitors migrate into the subventricular zone (SVZ), divide a few times, and give rise to more neurons (Figure 2a). It has been shown that some neural stem cells become slowly dividing or quiescent during embryonic stages and remain as adult neural stem cells (Fuentealba et al, 2015;Furutachi et al, 2015) while others become quiescent postnatally (Berg et al, 2019). Neurons are formed in an inside-out pattern such that inner-layer neurons are generated first, followed by outer-layer neurons.…”

“…After producing neurons, radial glial cells finally differentiate into glial cells (oligodendrocytes and astrocytes), although some of them are maintained as neural stem cells in the postnatal and adult brain. It has been shown that some neural stem cells become slowly dividing or quiescent during embryonic stages and remain as adult neural stem cells (Fuentealba et al, 2015;Furutachi et al, 2015) while others become quiescent postnatally (Berg et al, 2019).…”

Single cell transcriptomic analysis revealed long-lasting adverse effects of prenatal tamoxifen administration on neurogenesis in prenatal and adult brains

“…TAM inducible CreER/LoxP system laid the foundations of significant discoveries in adult and embryonic neural stem cell fate mapping (Berg et al, 2019;Bond et al, 2015;Fuentealba et al, 2015;Gao et al, 2014), gene functions (Kuo et al, 2006), as well as neuronal subtypes and activity dependent neural circuitry (Kim et al, 2017;Paul et al, 2017;Ye et al, 2016). Is the potential side effect of TAM a vulnerable Achille's heel to cell lineage tracing and/or genetic targeting studies?…”

“…Empirically, administration of TAM or its active metabolite, 4-hydroxytamoxifen (4-OH-TAM) by either gavage (~1.5-10mg TAM/mouse) or intraperitoneal (IP) injections (~750g-1.5mg TAM/mouse) to pregnant mice led to embryonic lethality and/or dystocia. To obtain postnatal offspring, it is frequently required that a caesarian section is performed followed by fostering (Berg et al, 2019;Gao et al, 2014;Georgala et al, 2011;Imayoshi et al, 2010;Lizen et al, 2015; Paul S. Danielian, 1998).…”

Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis

“…In mice, proliferative dentate precursor cells enter quiescence during the 2 nd week after birth. By the end of the second postnatal week, quiescent dentate precursors have acquired the elongated and branched morphology of adult NSCs and the DG has acquired its adult structure (Li et al, 2013;Nicola et al, 2015;Noguchi et al, 2019;Berg et al, 2019). There is therefore a clear transition from developmental neurogenesis, that extends from midembryogenesis to the second postnatal week, to adult hippocampal neurogenesis that starts around postnatal day 14 (P14) and continues throughout life (Hochgerner et al, 2018;Noguchi et al, 2019;Berg et al, 2019).…”