脳科学辞典

脳の領域化

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笹井 紀明
奈良先端科学技術大学院大学
DOI：10.14931/bsd.9270　原稿受付日：2020年7月18日　原稿完成日：20XX年X月X日
担当編集委員：花嶋 かりな（早稲田大学 教育・総合科学術院 先進理工学研究科）

Regionalization of the brain）

　脳領域に存在する細胞の種類は極めて多岐にわたるが、その多様化・領域化は、脳発生の初期から起こり始めている。この項では、領域化に関与する転写因子と、その発現を誘導するオーガナイザーや分泌因子を中心に、脊椎動物の脳が神経外胚葉から各細胞が分化し、組織内で領域化されるまでの過程を中心に記述する。 　なお、本項目の内容は、別項目の「前後軸」（高橋）とも一部重複する。

初期胚におけるおおまかな領域の決定 　脊椎動物では、原腸形成期に胚の背側に神経板が出現し、原腸形成期の後半からOtx2（Orthodenticle Homeobox 2）という転写因子が、頭部神経板領域（将来前脳・中脳領域に分化する部分）に発現する [1] 。Otx2はほかに胚盤葉上層、眼にも発現しており、それぞれに特異的なエンハンサー領域が存在する [2] 。一方、後脳には別の転写因子Gbx2が発現し [3] 、Otx2のエンハンサー領域の一部に結合してOtx2の発現領域を制限する [4] 。

２次オーガナイザー領域の形成 　脳のさらなる領域化には、以下の３つのオーガナイザー領域（シグナリングセンターとして分泌因子を産生する領域）が存在し、FGFやShh、Wntなどの分泌因子を発現し、脳の領域を決定している。（なお以下のオーガナイザー領域の日本語名は、英語名を直訳した試訳である）。

2-1. Anterior Neural Ridge（ANR）：前部神経端 　この領域自体は非神経性細胞からなっているが、主にFGF8を発現しており、転写因子BF-1の発現を誘導する。BF-1はANRの機能を相補する（ANRがなくてもBF-1が発現したら終脳が正常に発生する）ため、BF-1はANRによって誘導される主要な因子である [5] 。

2-2. Zona limitans intrathalamica（ZLI） 　この部分は、前脳から発生した大脳を２つの異なる性質を持つ領域に分ける領域である。大脳部分はプロソメアという区分に従って３つに分割することができるが、前部から順に、p3, p2, p1と分けられる領域のうち、p2とp3を分けるものがZLIである。ZLIが発現するのはソニック・ヘッジホッグ（Sonic Hedgehog; Shh）である[6] 。ZLIの前後では、Shhに対する細胞の反応性が異なり、ZLIよりも前部ではDlx2が、後部ではIrx3、Gbx2の発現が誘導される。

2-2. Isthmic Organiser（IsO）：峡部オーガナイザー Midbrain-Hindbrain Boundary（MHB）：中脳／後脳境界 　この領域からは、FGF8やWnt1などの分泌因子が分泌され、中脳や小脳に発現する転写因子を発現誘導する。MHBにおけるFGF8やWnt1の発現には転写因子Lmx1bが必要だと言われている [7] 。FGF8はMHBの前後である中脳と後脳に発現する遺伝子を誘導する一方、Wnt1は細胞の増殖などに関与していると考えられている [8] 。

脳の各領域に発現する転写因子

　上述の２次オーガナイザー領域から分泌されたFGFやWntなどのシグナル因子により、転写因子が脳の特定の領域に発現し、各領域を特徴付けている。これらの転写因子のノックアウトマウスは、一部は脳領域の一部を欠損することになり、脳の発達または成長に大きな影響を及ぼすために胚性致死となる。一方、これらの転写因子は、免疫細胞、内分泌系、腎臓や精巣、肺などにも発現する。したがって、各遺伝子の単純なノックアウトでは、表現型が脳以外の領域にも見られるものがある（Irx3、Nkx2.1、Sim-2、Lmx1b、BF2など）。これらの例では、脳領域における機能を明らかにするために、脳特異的なノックアウト（条件付き遺伝子ノックアウト：コンディショナルノックアウト）が作成され、解析が進んでいる。

（図１）脳の領域化と、運命決定図。胚の背側からの模式図。Developmental Biology（ギルバート・バレッシ著）第11巻をもとに作成。 （図２）前後軸、背腹軸に沿った分泌因子、転写因子の一部の発現領域。[8] [9] [10] などを参考にして作成。 （図３）脳で領域特異的に発現する転写因子の性質・機能と、その変異がヒトにもたらす疾患。OMIM（Online Mendelian Inheritance in Man; https://www.omim.org）や NIH Genetics Home Reference（https://ghr.nlm.nih.gov)を参考に作成。 各参考論文 [11] [12] [13] [14] [15] [16] 引用エラー: 無効な <ref> タグです。数が多すぎるなどの理由で名前が無効です [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] 引用エラー: 無効な <ref> タグです。数が多すぎるなどの理由で名前が無効です [37] [38] [39] [40] [41] [42] {Winslow, 2011 #58} [43] [44] [45] [46] [47] [1] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [7] [64]

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    Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development (Cambridge, England), 121(10), 3279-90. [PubMed:7588062] [WorldCat]
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