小脑,眼,颅面,生殖器(COFG)综合征是由MAB21L1突变引起的人类遗传疾病。具有Mab21l1-null突变的COFG小鼠模型会导致严重的小眼症和font门骨生成困难,类似于人类患者的症状。典型的症状之一是男婴阴囊发育不全,而雄性Mab21l1-null小鼠表现出发育不良的包皮腺,颅骨阴囊褶皱的啮齿动物特异性衍生物。然而,目前尚不清楚MAB21Ll在小鼠和人类的外生殖器中的何处以及如何起作用。在这里我们展示,在新生儿阶段,MAB21L1在外生殖器中的表达仅限于两个间充质细胞群-阴囊和唇皮肤下方以及包皮和阴蒂腺(PG/CG)周围。Mab21l1-/-幼崽的形态测量分析显示阴囊的外部大小显着减少,外阴,CG,还有PG。在PG和CG周围地区,在几种细胞外基质蛋白的细胞密度和免疫反应性信号中,岛周间充质细胞显示出急剧下降(例如,胶原蛋白I,纤连蛋白,和蛋白聚糖),以及它们降低的Ki67阳性细胞增殖指数。在Mab21l1-/-PG/CG中,血管化减少,腺体上皮显示萎缩,基底膜沿基底表面不连续,细胞质中糖原积累缺陷。在分离的PG的5天器官培养下,Mab21l1-/-外植体在体外显示出弱的生长和腺体结构的保留。然而,添加外源性Matrigel可以部分挽救这种组织自主表型,显示与野生型外植体相似的腺体形态。这些发现表明,MAB21L1间充质细胞在为周围外生殖器的腺体生长和形态发生提供营养ECM支持中起着至关重要的作用。
The cerebellar, ocular, craniofacial, and genital (COFG) syndrome is a human genetic disease that is caused by MAB21L1 mutations. A COFG mouse model with Mab21l1-null mutation causes severe microphthalmia and fontanelle dysosteogenesis, similar to the symptoms in human patients. One of the typical symptoms is scrotal agenesis in male infants, while male Mab21l1-null mice show hypoplastic preputial glands, a rodent-specific derivative of the cranial scrotal fold. However, it is still unclear where and how MAB21Ll acts in the external genitalia in both mice and humans. Here we show that, at the neonatal stage, MAB21L1 expression in the external genitalia was restricted to two mesenchymal cell populations-underneath the scrotal and labial skin and around the preputial and clitoral glands (PG/CG). Morphometric analyses of the Mab21l1-/- pups revealed a significant reduction in the external size of the scrotum, vulva, and CG, as well as PG. In the periglandular region around PG and CG, the periglandular mesenchymal cells showed a drastic reduction in both cell density and immunoreactive signals for several extracellular matrix proteins (e.g., collagen I, fibronectin, and proteoglycans), together with their reduced Ki67-positive cell proliferation index. In the Mab21l1-/- PG/CG, together with reduced vascularization, the glandular epithelia displayed atrophy with discontinuous basal lamina along the basal surface and defective glycogen accumulation in their cytoplasm. Under a 5-day organ culture of the isolated PG, the Mab21l1-/- explants showed poor outgrowth and retention of the glandular structure in vitro. However, the addition of exogenous Matrigel could partially rescue such tissue-autonomous phenotypes, showing glandular morphology similar to that of the wild-type explants. These findings suggest that MAB21L1+ mesenchymal cells play a crucial role in providing nutrient ECM support for glandular outgrowth and morphogenesis in the peripheral external genitalia.