Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.
Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.
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DOI：
10.1007/s00401-021-02355-7
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发表时间：
2021-10
影响因子：
12.7
通讯作者：
Millen KJ
中科院分区：
文献类型：
--
作者：
Haldipur P;Bernardo S;Aldinger KA;Sivakumar T;Millman J;Sjoboen AH;Dang D;Dubocanin D;Deng M;Timms AE;Davis BD;Plummer JT;Mankad K;Oztekin O;Manganaro L;Guimiot F;Adle-Biassette H;Russo R;Siebert JR;Kidron D;Petrilli G;Roux N;Razavi F;Glass IA;Di Gioia C;Silvestri E;Millen KJ
Dandy-Walker畸形(DWM)和小脑蠕虫发育不全(CVH)是超声和产前或产后MRI诊断的常见人类小脑畸形。使用特定的放射学标准来区分它们，但对它们不同的发育疾病机制知之甚少。我们收集了诊断为DWM和CVH的产前病例，并研究了小脑形态计量学，随后进行了组织学和免疫组织化学分析。除此之外，还进行了激光捕获显微解剖和小脑菱形嘴唇的RNA测序，以评估DWM和对照样本的转录组的变化。我们的放射学发现证实，所研究的病例属于可接受的DWM生物测量范围。我们的组织病理学分析指出，在所有检查的DWM病例中，叶状结构减少和下部蠕虫发育不良是共同的特征。我们还发现，在DWM中，驱动后部蠕虫生长和维持的背侧干细胞区--菱形唇区--被特异性破坏，祖细胞池的增殖和自我更新减少，血管系统改变，所有这些都得到了转录学分析的证实。我们提出了一个统一的模型来解释弥漫性脑病的发病机制。我们假设，通过异常的血管形成和/或直接的侮辱，菱形嘴唇的发育被破坏，这会导致菱形唇祖库的增殖减少和扩张失败，从而导致下唇不成比例的发育不良和发育不良。发育中的菱形唇部受损的时间(14周前或14周后)决定了发育不全的程度，并区分了弥漫性唇裂和脑血管性血肿。
Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.
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影响因子：
30.8
作者：
Aldinger, Kimberly A.;Lehmann, Ordan J.;Hudgins, Louanne;Chizhikov, Victor V.;Bassuk, Alexander G.;Ades, Lesley C.;Krantz, Ian D.;Dobyns, William B.;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
影响因子：
3
作者：
Bernardo, Silvia;Vinci, Valeria;Manganaro, Lucia
通讯作者：
Manganaro, Lucia
影响因子：
3.5
作者：
Poretti, Andrea;Boltshauser, Eugen;Huisman, Thierry A. G. M.
通讯作者：
Huisman, Thierry A. G. M.
小鼠和人类FOXC1依赖的dandy-walker小脑畸形中的表型结局提出了共同的机制。
影响因子：
7.7
作者：
Haldipur P;Dang D;Aldinger KA;Janson OK;Guimiot F;Adle-Biasette H;Dobyns WB;Siebert JR;Russo R;Millen KJ
通讯作者：
Millen KJ
影响因子：
25
作者：
Aldinger KA;Thomson Z;Phelps IG;Haldipur P;Deng M;Timms AE;Hirano M;Santpere G;Roco C;Rosenberg AB;Lorente-Galdos B;Gulden FO;O'Day D;Overman LM;Lisgo SN;Alexandre P;Sestan N;Doherty D;Dobyns WB;Seelig G;Glass IA;Millen KJ
通讯作者：
Millen KJ