Neuroscience Letters 453 (2009) 21–26 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Selective upregulation of 3-phosphoglycerate dehydrogenase (Phgdh) expression in adult subventricular zone neurogenic niche Masami O. Kinoshita a,d , Yoko Shinoda a , Kazuhisa Sakai b , Tsutomu Hashikawa b , Masahiko Watanabe e , Takeo Machida d , Yoshio Hirabayashi a , Shigeki Furuya a,c,∗ a Hirabayashi Research Unit, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan b Laboratory for Neural Architecture, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan c Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, 6-10-1 Hakozaki, Fukuoka City, Fukuoka 812-8581, Japan d Department of Regulation Biology, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan e Department of Anatomy, Hokkaido University Medical School, Sapporo 060-8638, Japan article info Article history: Received 15 October 2008 Received in revised form 21 January 2009 Accepted 1 February 2009 Keywords: l-Serine Adult neurogenesis Subventricular zone Neural stem/progenitor cells abstract In the adult rodent brain, constitutive neurogenesis occurs in two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus, where multipotent neural stem/progenitor cells generate new neurons. Using Western blotting and immuno- histochemistry for established markers, we demonstrated that the expression of 3-phosphoglycerate dehydrogenase (Phgdh), an enzyme involved in de novo synthesis of l-serine, was upregulated in the SVZ. The expression was selective to cells having morphological features and expressing markers of astrocyte- like primary neural stem cells (type B cells) and their progeny, actively proliferating progenitors (type C cells). By contrast, Phgdh protein expression was virtually absent in committed neuronal precursors (type A cells) derived from type C cells. High levels of Phgdh were also expressed by glial tube cells located in the rostral migratory stream (RMS). Interestingly, ensheathment of type A cells by these Phgdh-expressing cells was persistent in the SVZ and RMS, suggesting that l-serine mediates trophic support for type A cells via these glial cells. In vitro neurosphere assays confirmed that growth-factor-responsive, transient amplifying neural progenitors in the SVZ, but not differentiated neurons, expressed Phgdh. In the aged brain, a decline in Phgdh expression was evident in type B and C cells of the SVZ. These observations support the notion that availability of l-serine within neural stem/progenitor cells may be a critical factor for neurogenesis in developing and adult brain. © 2009 Elsevier Ireland Ltd. All rights reserved. In the mammalian brain, neurogenesis continues throughout adult- hood in two restricted areas, the subventricular zone (SVZ) of the lateral wall of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), where new neurons are generated from multipotent neural stem/progenitor cells and are functionally integrated into existing neuronal circuits [14,21,35]. Over the past decade, progress in understanding the cellular archi- tecture and regulatory signaling events in these two neurogenic niches have shed light on the basic mechanism and the functional significance of adult neurogenesis. However, little is known about the cellular intrinsic factors that support lifelong neurogenesis by adult neural progenitor cells. ∗ Corresponding author at: Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, 6-10-1 Hakozaki, Fukuoka City, Fukuoka 812- 8581, Japan. Fax: +81 92 642 7604. E-mail addresses: shigekifur@brs.kyushu-u.ac.jp, valsenoble@gmail.com (S. Furuya). We demonstrated previously that 3-phosphoglycerate dehydro- genase (Phgdh), which catalyzes the first step of the phosphorylated pathway in the de novo synthesis of l-serine, is expressed prefer- entially in neuroepithelium/radial glia cells in embryonic brain and later in astrocytes [33]. In embryonic brain, neuroepithelium/radial glia cells have been well documented to function as embryonic mul- tipotent neural progenitor cells that generate neurons, astrocytes, and oligodendrocytes [14,24]. In adult brain, we observed in the hippocampal SGZ actively proliferating neural progenitor-like cells that express Phgdh [33]. Seri et al. also reported that Phgdh local- izes to radial astrocytes, presumable adult neuronal stem cells, in the SGZ [28]. l-Serine is a necessary precursor for synthesis of a variety of biomolecules important for cell survival and proliferation. In addition to proteins, these molecules include other amino acids including cysteine, phosphatidylserine, sphingolipids, purines, and thymidines, all of which are directly linked to cellular replication [9,13,30]. By generating mice that carry targeted disruption of Phgdh, we provided definitive in vivo evidence showing that Phgdh-dependent 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.02.001