Abstract

Ras homology enriched in the brain (Rheb) is well established as a critical regulator of cell proliferation and differentiation in response to growth factors and nutrients. However, the role of Rheb1 in limb development remains unknown. Here, we found that Rheb1 was dynamically expressed during the proliferation and differentiation of chondrocytes in the growth plate. Given that Prrx1⁺ limb-bud-like mesenchymal cells are the source of limb chondrocytes and are essential for endochondral ossification, we conditionally deleted Rheb1 using Prrx1-Cre and found a limb dwarfism in Prrx1-Cre; Rheb1^fl/fl mice. Normalized to growth plate height, the conditional knockout (cKO) mice exhibited a significant decrease in column count of proliferative zones which was increased in hypertrophic zones resulting in decreased growth plate size, indicating abnormal endochondral ossification. Interestingly, although Rheb1 deletion profoundly inhibited the transcription factor Sox9 in limb cartilage; levels of runx2 and collagen type 2 were both increased. These novel findings highlight the essential role of Rheb1 in limb growth and indicate a complex regulation of Rheb1 in chondrocyte proliferation and differentiation.

中文翻译：

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Rheb1 通过调节生长板中的软骨形成来促进肢体生长

摘要

大脑中富集的 Ras 同源性 (Rheb) 被认为是响应生长因子和营养物质的细胞增殖和分化的关键调节因子。然而，Rheb1 在肢体发育中的作用仍不清楚。在这里，我们发现Rheb1在生长板中软骨细胞的增殖和分化过程中动态表达。鉴于Prrx1 ⁺肢芽样间充质细胞是肢体软骨细胞的来源，并且对于软骨内骨化至关重要，我们使用Prrx1-Cre条件性删除Rheb1 ，并在Prrx1-Cre中发现肢体侏儒症；Rheb1 ^fl/fl小鼠。以生长板高度标准化后，条件敲除（cKO）小鼠表现出增殖区柱数显着减少，肥大区柱数增加，导致生长板尺寸减小，表明软骨内骨化异常。有趣的是，尽管Rheb1缺失深刻抑制了肢体软骨中的转录因子Sox9；runx2 和 2 型胶原蛋白的水平均有所增加。这些新发现强调了 Rheb1 在肢体生长中的重要作用，并表明 Rheb1 在软骨细胞增殖和分化中的复杂调节。