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.

Dandy-Walker 畸形 (DWM) 和小脑蚓部发育不全 (CVH) 是常见的公认的人类小脑畸形，通过超声和​​产前或产后 MRI 诊断。使用特定的放射学标准来区分它们，但对它们的不同发育疾病机制知之甚少。我们获得了诊断为 DWM 和 CVH 的产前病例，并研究了小脑形态测量学，然后进行了组织学和免疫组织化学分析。这辅以激光捕获显微切割和小脑菱形唇的 RNA 测序，这是一个短暂的祖区，以评估 DWM 与对照样品的转录组改变。我们的放射学研究结果证实，所研究的病例属于 DWM 可接受的生物识别范围。我们的组织病理学分析指出，在所有检查过的 DWM 病例中，叶片减少和下蠕虫发育不全是共同特征。我们还发现菱形唇，一种驱动后蚓部生长和维持的背侧干细胞区，在 DWM 中被特别破坏，祖细胞池的增殖和自我更新减少，血管系统发生改变，所有这些都通过转录组学分析得到证实. 我们为 DWM 的发育发病机制提出了一个统一的模型。我们假设菱形唇发育受到异常血管化和/或直接损伤的破坏，导致菱形唇祖细胞增殖减少和扩张失败，导致下蚓部不成比例的发育不全和发育不良。