Sawamoto Lab 澤本研究室

Subventricular Zone-Derived Neural Progenitor Cells Migrate Along a Blood Vessel Scaffold Toward the Post-Stroke Striatum

Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H, Sawamoto K.

The subventricular zone (SVZ) of the adult brain contains neural stem cells that have the capacity to regenerate new neurons after various insults. Brain ischemia causes damage to brain tissue and induces neural regeneration together with angiogenesis. We previously reported that, after ischemic injury in mice, SVZ-derived neural progenitor cells (NPCs) migrate into the striatum, and these NPCs are frequently associated with blood vessels in the regenerating brain tissue. Here we studied the role of blood vessels during the neural regeneration in more detail. BrdU administration experiments revealed that newly generated NPCs were associated with both newly formed and pre-existing blood vessels in the ischemic striatum, suggesting that the angiogenic environment is not essential for the neuron-blood-vessel interaction. To observe migrating NPCs and blood vessels simultaneously in damaged brain tissue, we performed live imaging of cultured brain slices after ischemic injury. In this system, we virally labeled SVZ-derived NPCs in Flk1-EGFP knock-in mice, in which the blood vessels are labeled with EGFP. Our results provide direct evidence that SVZ-derived NPCs migrate along blood vessels from the SVZ toward the ischemic region of the striatum. The leading process of the migrating NPCs was closely associated with blood vessels, suggesting that this interaction provides directional guidance to the NPCs. These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region.

Stem Cells 2010 Jan 13. [Epub ahead of print]

Full Text (open access)

表紙のイラスト：マウス成体脳室下帯におけるニューロンの産生

脳室下帯の神経幹細胞（青）が産生するニューロン（赤）は嗅球へ移動して成熟する。
Kaneko, N and Sawamoto, K. (2009)
Adult neurogenesis and its alteration under pathological conditions
Neurosci. Res. 63: 155-164. (REVIEW ARTICLE)

【博士課程・修士課程の大学院生として研究に参加できます。】
学位論文のテーマとしては、例えば以下のような課題があります。
・げっ歯類・霊長類の成体脳室下帯におけるニューロン新生・移動メカニズムの解析
・感覚入力による成体嗅球ニューロン産生の制御機構の解析
・脳室上衣細胞の成熟と繊毛運動による液流発生のメカニズムと意義の解明
・ゼブラフィッシュの遺伝学的手法を用いたニューロン新生メカニズムの解明
・虚血性疾患モデルにおける神経再生メカニズムの解明と治療法の開発

問いあわせ：sawamoto@med.nagoya-cu.ac.jpまで。研究室見学も可能です。

The Journal of Neuroscience, November 21, 2007, 27(47):12829-12838

Cyclin-Dependent Kinase 5 Is Required for Control of Neuroblast Migration in the Postnatal Subventricular Zone

Yuki Hirota, Toshio Ohshima, Naoko Kaneko, Makiko Ikeda, Takuji Iwasato, Ashok B. Kulkarni, Katsuhiko Mikoshiba, Hideyuki Okano, and Kazunobu Sawamoto

At the lateral wall of the lateral ventricles in the adult rodent brain, neuroblasts form an extensive network of elongated cell aggregates called chains in the subventricular zone and migrate toward the olfactory bulb. The molecular mechanisms regulating this migration of neuroblasts are essentially unknown. Here, we report a novel role for cyclin-dependent kinase 5 (Cdk5), a neuronal protein kinase, in this process. Using in vitro and in vivo conditional knock-out experiments, we found that Cdk5 deletion impaired the chain formation, speed, directionality, and leading process extension of the neuroblasts in a cell-autonomous manner. These findings suggest that Cdk5 plays an important role in neuroblast migration in the postnatal subventricular zone.

Key words: Cdk5; neuroblast; migration; subventricular zone; rostral migratory stream; postnatal neurogenesis

Stem Cells. 2007 Aug 2; PMID: 17673525

β-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone

Kazuhide Adachi, Zaman Mirzadeh, Masanori Sakaguchi, Toru Yamashita, Tania Nikolcheva, Yukiko Gotoh, Gary Peltz, Leyi Gong, Takeshi Kawase, Arturo Alvarez-Buylla, Hideyuki Okano, Kazunobu Sawamoto

Abstract

The subventricular zone (SVZ) is the largest germinal zone in the mature rodent brain, and it continuously produces young neurons that migrate to the olfactory bulb. Neural stem cells in this region generate migratory neuroblasts via highly proliferative transit-amplifying cells. The Wnt/β-catenin signaling pathway partially regulates the proliferation and neuronal differentiation of neural progenitor cells in the embryonic brain. Here, we studied the role of beta-catenin signaling in the adult mouse SVZ. β-catenin-dependent expression of a destabilized form of green fluorescent protein was detected in progenitor cells in the adult SVZ of Axin2-d2EGFP reporter mice. Retrovirus-mediated expression of a stabilized β-catenin promoted the proliferation of Mash1+ cells and inhibited their differentiation into neuroblasts. Conversely, the expression of Dkk1, an inhibitor of Wnt signaling, reduced the proliferation of Mash1+ cells. In addition, an inhibitor of GSK3 promoted the proliferation of Mash1+ cells, and increased the number of new neurons in the olfactory bulb 14 days later. These results suggest that β-catenin signaling plays a role in the proliferation of progenitor cells in the SVZ of the adult mouse brain.

Key Words. β-catenin, neurogenesis, cell proliferation, subventricular zone, olfactory bulb, Mash1