Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-Related Transcripts.

Christin Weissleder,Samantha J Fung,Glenda M Halliday,Guy Barry,Maree J Webster,Cynthia Shannon Weickert,Matthew W Wong,Kay L Double

doi:10.3389/fnagi.2016.00274

Abstract

Neuroblasts exist within the human subependymal zone (SEZ); however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We found evidence of dividing cells in the human SEZ (n D 50) in conjunction with a dramatic age-related decline (21-103 years) of mRNAs indicative of proliferating cells (Ki67) and immature neurons (doublecortin). Microglia mRNA (ionized calcium-binding adapter molecule 1) increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1), astrocytes (vimentin and pan-glial fibrillary acidic protein), and oligodendrocytes (oligodendrocyte lineage transcription factor 2) remained stable. Epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF2) mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα), EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4) and FGF receptor 1 (FGFR1) mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte marker expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2, and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.

Highlights

The formation of new neurons from stem cells in the subependymal zone (SEZ, subventricular zone) lining the lateral ventricles persists throughout life in many mammals (Altman, 1969); the existence of this neurogenic zone in adult humans is still debated
Brain pH negatively correlated with epidermal growth factor receptor (EGFR) (r = −0.40, p = 0.004), fibroblast growth factor 2 (FGF2) (r = −0.36, p = 0.01) and FGF receptor 1 (FGFR1) mRNAs (r = −0.29, p = 0.04), whereas post-mortem interval (PMI) showed a negative relationship to EGFR (r = −0.36, p = 0.009), FGF2 (r = −0.35, p = 0.01), and pan-glial fibrillary acidic protein (GFAP) mRNAs (r = −0.29, p = 0.04)
Co-localization of cell proliferation markers with the neuron-specific class III β-tubulin and DCX in the adult macaque and human SEZ suggest that proliferating cells produce immature neurons (Kornack and Rakic, 2001; Wang et al, 2011), we found that proliferative events and neuronal differentiation may not be tightly coupled in the adult human SEZ

Summary

Introduction

The formation of new neurons from stem cells in the subependymal zone (SEZ, subventricular zone) lining the lateral ventricles persists throughout life in many mammals (Altman, 1969); the existence of this neurogenic zone in adult humans is still debated. The astrocytic ribbon represents a neurogenic niche in which stem cells with astrocyte-like properties reside and can generate transit amplifying precursor cells, which in turn produce neuroblasts that can migrate along the rostral migratory stream into the olfactory bulb (Doetsch et al, 1997). Previous reports provide evidence for cell proliferation and the presence of both multipotent precursor cells and immature neurons in the postnatal human SEZ (Weickert et al, 2000; Sanai et al, 2004, 2011; Curtis et al, 2005; Quinones-Hinojosa et al, 2006; Barry et al, 2015). There is a clear need for further studies examining the extent of neurogenesis in the human SEZ over the entire adult lifespan

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