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。

(編集部コメント:…について記述すると行った表現ではなく、抄録をお願いいたします。)

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)。

前部神経端

Anterior Neural Ridge(ANR)  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]

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。

峡部オーガナイザー

Isthmic Organiser(IsO): 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。

転写因子 遺伝子名 転写因子としてのクラス 脳の発生期における発現領域 変異マウスの表現型 ヒト疾患との関連 論文
"ARX
(Aristaless-related Homeobox)" ホメオボックス型 終脳(背側)、前脳(視床) "新生児死亡(マウスの系統による):脳細胞の増殖抑制により、前脳が矮小化。
脳領域のみのコンディショナルノックアウトでは、腹側脳領域の異常拡大。" 精神遅滞、てんかん、など 11971879 , 12379852 , 14561778 , 30659230 , 18509041
"Dlx2
(Distal-less homeobox 2)" ホメオボックス型 前脳(脳室帯、脳室下帯) "
Dlx1/2のダブルノックアウトが新生児死亡:終脳の神経分化が抑制され、グリア細胞が増加。
網膜の神経節細胞層がアポトーシスを起こす。" Dix2遺伝子(2番染色体上)を含む領域が自閉症の発症と相関が高いことが示唆されている 7590232 , 15604100 , 18728693 , 17678855
"Emx1
(Empty Spiracles Homeobox 1)" ホメオボックス型 前脳 生存可能:脳梁(corpus callosum)欠損 "カルマン症候群(Kallmann syndrome:
嗅覚低下と性腺機能低下)への関与が示唆されている" 9006071 , 20887964 , 10906797 , 8743751
"Emx2
(Empty Spiracles Homeobox 2)" ホメオボックス型 前脳 皮質領域の矮小化 裂脳症(schizencephaly) 15294144 , 8528262 , 10906797 , 8743751
"En-1
(Engrailed homeobox-1)" ホメオボックス型 中脳と小脳(R1) 胚性致死:視蓋と小脳の発生不全 パーキンソン病 7925010 , 26459030 , 26879466
"En-2
(Engrailed homeobox-2)" ホメオボックス型 中脳、小脳 生存可能:神経行動学的、神経化学的異常 "自閉症スペクトラム障害に関与すると示唆されて
いる" 16935268 , 16252243 , 26220976
"FEZ/FEZF1/Znf312b
(Forebrain Embryonic Zinc-finger 1)" "C2H2-type
zinc フィンガー" 嗅球、前脳、外套層 "FEZF2とのダブルノックアウトにより、視床、大脳
の発生が停止" "カルマン症候群(Kallmann syndrome):
嗅覚低下と性腺機能低下" 16971467
"FoxD1/BF2
(Brain Factor-2)" Winged-Helix型 前脳 "新生児死亡:腎臓の間葉系間質細胞の発生に必要
胚発生期では、視床下部前部の神経前駆細胞の分化が抑制される" 8666231 , {Newman, 2018}
"FoxG1/BF-1
(Brain Factor-1)" Winged-Helix型 終脳 新生児死亡:終脳の矮小化 Rett症候群 7605629
"Gbx2
(Gastrulation Brain Homeobox 2)" ホメオボックス型 中脳、後脳(R1-R3) R3領域が矮小化 大腸癌(Colon Small Cell Carcinoma)、Optiz-G/BBB Syndrome(オピッツ症候群:脳、顔面、心臓、生殖器などの正中部形成不全) 9247335 , 16651541
"Irx3
(Iroquois homeobox 3)" ホメオボックス型 中脳、視蓋前域、視床 Irx5とのダブルノックアウトで心臓の一部(流出部)の形成異常が見られている 肥満への関与が示唆されている 9486539 , 22992950 , 31538128 , 32035736
"Lhx2
(LIM/homeobox transcription factor 2)" LIMホメオボックス型 前脳 眼・前脳の発生、嗅神経細胞の分化異常 (報告なし) 15173589 , 29522720 , 9247336
Lmx1b LIMホメオボックス型 中脳、視蓋前域、視床 "Isthmic Organiserの形成が阻害される
分化した糸球体上皮細胞(podocyte)の消滅" ネイル・パテラ症候群(爪膝蓋骨症候群:爪の変形や腎臓障害など) 23990680 , 12498783 , 10751174 , 17166916
Nkx2.1 ホメオボックス型 視床下部 "新生児死亡:呼吸器官と肺の形成異常
視床下部におけるメラノコルチン産生(Pomc陽性)細胞の減少" 肺腺癌の重篤化に関わっている · 10706142 , 21471965 , 30886014
Nkx6.1 ホメオボックス型 中脳底板 膵臓のベータ細胞が減少 Nkx6.1の強制発現ががん細胞の浸潤を防ぐ効果があると報告されている 11076772 , 24035389
"Otx2
(Orthodenticle homeobox 2)" ホメオボックス型 前脳、中脳 胚性致死:前脳、中脳欠損 小眼球、網膜変性、複合下垂体ホルモン欠損症 10490025 , 25293953 , 24167467 , 22577225 , 7588062
"Pax2
(Paired box gene 2)" paired box 中脳、小脳領域、発生途上の眼、耳 耳の形成異常、視神経投射異常 " 腎細胞においてPax2の恒常的な発現が糸球体硬化
(glomerulosclerosis)を引き起こす" 8951055 , 12915483
"Sim-1
(Single-minded homolog 1)" bHLH-PASドメイン 視床下部 新生児死亡:視索上核(supraoptic)と室傍核(paraventricular)の形成不全 食欲過剰による肥満 24773343 , 10587584 , 11448938
"Sim-2
(Single-minded homolog 2)" bHLH-PASドメイン 視床下部前部 新生児死亡:肺機能不全 Sim2遺伝子の増幅によりダウン症が引き起こされると示唆されている 12024028 , 7568099 , 14988428
"Six3
(Sine Oculis Homeobox 3)" ホメオボックス型 発生初期には神経板、眼球、眼杯、中期以降は眼、耳、中脳、視蓋前側、ZLI(zona limitans intrathalamica)、視床外腹側核(rostral ventral thalamus) 眼を含む前脳の前部を欠損 2型全前脳胞症(Holoprosencephaly) 10369266 , 30485816 , 12569128 , 20890044

関連項目


(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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