Autism NPCs from both idiopathic and CNV 16p11.2 deletion patients exhibit dysregulation of proliferation and mitogenic responses.
Autism NPCs from both idiopathic and CNV 16p11.2 deletion patients exhibit dysregulation of proliferation and mitogenic responses.
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DOI：
10.1016/j.stemcr.2022.04.019
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发表时间：
2022-06-14
影响因子：
5.9
通讯作者：
DiCicco-Bloom, Emanuel
中科院分区：
文献类型：
--
作者：
Connacher, Robert;Williams, Madeline;Prem, Smrithi;Yeung, Percy L.;Matteson, Paul;Mehta, Monal;Markov, Anna;Peng, Cynthia;Zhou, Xiaofeng;McDermott, Courtney R.;Pang, Zhiping P.;Flax, Judy;Brzustowicz, Linda;Lu, Che-Wei;Millonig, James H.;DiCicco-Bloom, Emanuel
神经前体细胞（NPC）功能障碍一直与自闭症有关。来自两个自闭症组（三个特发性[I-ASD]和两个16p11.2缺失[16 pDel]）的诱导多能干细胞（iPSC）衍生的NPC用于研究增殖是否通常被破坏。所有五个个体都显示缺陷，所有三个大头个体（两个16 pDel，一个I-ASD）都显示过度增殖，另外两个I-ASD受试者显示增殖不良。用bFGF挑战NPC，所有过度增殖的NPC显示钝化反应，而低增殖细胞的反应增加。mRNA表达研究表明，不同的途径可以导致相似的增殖表型。由于16 pDel删除了MAPK 3，因此测量了P-ERK。P-ERK在过度增殖的NPC中减少，但在低增殖的NPC中增加。虽然这些P-ERK的变化是不负责的表型，P-ERK和bFGF的反应是负相关的缺陷。最后，我们分析了iPSC，发现16 pDel显示过度增殖，而特发性iPSC是正常的。这些数据表明NPC增殖缺陷在ASD中是常见的。NPC增殖缺陷在特发性和16p11.2 CNV缺失型ASD中很常见。所有的大头I型ASD和16 pDel个体都有过度增殖的NPC。NPC对bFGF的增殖反应与P-ERK水平呈负相关。来自16 pDel个体的NPC和IPSC都表现出过度增殖。缺失型自闭症那些表现为大头畸形的过度增殖，而两个特发性个体表现为低增殖表型。有趣的是，16 pDel个体也表现出iPSC过度增殖缺陷。这些发现表明，增殖失调可能是多种形式自闭症的常见表型，并跨越发育阶段。
Neural precursor cell (NPC) dysfunction has been consistently implicated in autism. Induced pluripotent stem cell (iPSC)-derived NPCs from two autism groups (three idiopathic [I-ASD] and two 16p11.2 deletion [16pDel]) were used to investigate if proliferation is commonly disrupted. All five individuals display defects, with all three macrocephalic individuals (two 16pDel, one I-ASD) exhibiting hyperproliferation and the other two I-ASD subjects displaying hypoproliferation. NPCs were challenged with bFGF, and all hyperproliferative NPCs displayed blunted responses, while responses were increased in hypoproliferative cells. mRNA expression studies suggest that different pathways can result in similar proliferation phenotypes. Since 16pDel deletes MAPK3, P-ERK was measured. P-ERK is decreased in hyperproliferative but increased in hypoproliferative NPCs. While these P-ERK changes are not responsible for the phenotypes, P-ERK and bFGF response are inversely correlated with the defects. Finally, we analyzed iPSCs and discovered that 16pDel displays hyperproliferation, while idiopathic iPSCs were normal. These data suggest that NPC proliferation defects are common in ASD. NPC proliferation defects are common in idiopathic and 16p11.2 CNV-deletion ASD All macrocephalic I-ASD and 16pDel individuals have hyperproliferative NPCs NPC proliferative responses to bFGF correlate inversely with P-ERK levels Both NPCs and IPSCs derived from 16pDel individuals exhibit hyperproliferation In this article DiCicco-Bloom and colleagues show proliferation defects in neural precursor cells from idiopathic and 16p11.2-deletion forms of autism. Those exhibiting macrocephaly were hyperproliferative, while two idiopathic individuals displayed hypoproliferative phenotypes. Interestingly, 16pDel individuals also exhibited iPSC-hyperproliferative defects. These findings suggest that dysregulated proliferation may be a common phenotype in multiple forms of autism and span developmental stages.
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影响因子：
3.7
作者：
Wu DT;Seita Y;Zhang X;Lu CW;Roth MJ
通讯作者：
Roth MJ
影响因子：
25
作者：
Krishnan A;Zhang R;Yao V;Theesfeld CL;Wong AK;Tadych A;Volfovsky N;Packer A;Lash A;Troyanskaya OG
通讯作者：
Troyanskaya OG
影响因子：
4.2
作者：
Arsenault J;Gholizadeh S;Niibori Y;Pacey LK;Halder SK;Koxhioni E;Konno A;Hirai H;Hampson DR
通讯作者：
Hampson DR
自闭症中发现的 16p11.2 病变模型的剂量依赖性表型
DOI：
10.1073/pnas.1114042108
发表时间：
2011-10-11
影响因子：
11.1
作者：
Horev, Guy;Ellegood, Jacob;Mills, Alea A.
通讯作者：
Mills, Alea A.
影响因子：
4.8
作者：
ALESSI, DR;CUENDA, A;SALTIEL, AR
通讯作者：
SALTIEL, AR