The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and essential for the development and/or maintenance of multiple tissues and organs. SHP2 is involved in gastrointestinal (GI) epithelium development and homeostasis, but the underlying mechanisms remain elusive. While studying SHP2’s role in skeletal development, we made osteoblast‐specific SHP2 deficient mice using Osterix (Osx)‐Cre as a driver to excise Ptpn11 floxed alleles. Phenotypic characterization of these SHP2 mutants unexpectedly revealed a critical role of SHP2 in GI biology. Mice lacking SHP2 in Osx+ cells developed a fatal GI pathology with dramatic villus hypoplasia. OSTERIX, an OB‐specific zinc finger‐containing transcription factor is for the first time found to be expressed in GI crypt cells, and SHP2 expression in the crypt Osx+ cells is critical for self‐renewal and proliferation. Further, immunostaining revealed the colocalization of OSTERIX with OLFM4 and LGR5, two bona fide GI stem cell markers, at the crypt cells. Furthermore, OSTERIX expression is found to be associated with GI malignancies. Knockdown of SHP2 expression had no apparent influence on the relative numbers of enterocytes, goblet cells or Paneth cells. Given SHP2’s key regulatory role in OB differentiation, our studies suggest that OSTERIX and SHP2 are indispensable for gut homeostasis, analogous to SOX9’s dual role as a master regulator of cartilage and an important regulator of crypt stem cell biology. Our findings also provide a foundation for new avenues of inquiry into GI stem cell biology and of OSTERIX’s therapeutic and diagnostic potential.

中文翻译：

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SHP2通过修饰OSTERIX+隐窝干细胞自我更新和增殖调控肠上皮发育

由 PTPN11 编码的蛋白酪氨酸磷酸酶 SHP2 无处不在，对于多种组织和器官的发育和/或维持至关重要。SHP2 参与胃肠 (GI) 上皮发育和体内平衡，但其潜在机制仍然难以捉摸。在研究 SHP2 在骨骼发育中的作用时，我们使用 Osterix (Osx)-Cre 作为驱动因子来制备成骨细胞特异性 SHP2 缺陷小鼠，以切除 Ptpn11 floxed 等位基因。这些 SHP2 突变体的表型表征出人意料地揭示了 SHP2 在 GI 生物学中的关键作用。在 Osx+ 细胞中缺乏 SHP2 的小鼠出现了致命的胃肠道病理，伴有剧烈的绒毛发育不全。OSTERIX，一种含 OB 特异性锌指的转录因子，首次被发现在 GI 隐窝细胞中表达，隐窝 Osx+ 细胞中的 SHP2 和 SHP2 表达对于自我更新和增殖至关重要。此外，免疫染色揭示了 OSTERIX 与 OLFM4 和 LGR5（两种真正的 GI 干细胞标记物）在隐窝细胞中的共定位。此外，发现 OSTERIX 表达与胃肠道恶性肿瘤有关。SHP2 表达的抑制对肠上皮细胞、杯状细胞或潘氏细胞的相对数量没有明显影响。鉴于 SHP2 在 OB 分化中的关键调节作用，我们的研究表明 OSTERIX 和 SHP2 对于肠道稳态是必不可少的，类似于 SOX9 作为软骨的主要调节剂和隐窝干细胞生物学的重要调节剂的双重作用。我们的发现还为探索胃肠道干细胞生物学和 OSTERIX 治疗和诊断潜力的新途径奠定了基础。