Ferguson Gabriel B, Martinez-Agosto Julian A
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, Jonsson Comprehensive Cancer Center, UCLA Broad Stem Cell Center, Mattel Children's Hospital UCLA, USA.
Dev Biol. 2017 May 1;425(1):21-32. doi: 10.1016/j.ydbio.2017.03.016. Epub 2017 Mar 18.
The Drosophila lymph gland is a well-characterized hematopoietic organ in which a population of multipotent stem-like progenitors is maintained by a combination of signals from different cellular populations within the organ. The lymph gland serves as an ideal model both for the interrogation of signaling mechanisms involved in progenitor maintenance as well as a tool for the identification of novel regulatory mechanisms in the highly conserved process of hematopoiesis. Here, we demonstrate a requirement for the TEAD transcription factor Scalloped in the maintenance and proliferation of hematopoietic progenitors. We have characterized a novel population of hemocytes in the early lymph gland identified by the expression of Hand, Scalloped, and the PVR ligand PVF2. In this unique population, we show that Scalloped maintains PVF2 expression, which is required for hemocyte proliferation and achievement of normal lymph gland size. We further demonstrate that STAT signaling marks actively proliferating hemocytes in the early lymph gland, and inhibition of this pathway causes decreased lymph gland growth similar to loss of Scalloped and PVF2, demonstrating a requirement for PVR/STAT signaling in the regulation of lymph gland size. Finally, we demonstrate that Scalloped regulates PVR expression and the maintenance of progenitors downstream of PVR/STAT/ADGF signaling. These findings further establish the role of the TEAD family transcription factors in the regulation of important signaling molecules, and expand our mechanistic insight into the balance between progenitor maintenance and proliferation required for the regulation of lymph gland homeostasis.
果蝇淋巴腺是一个特征明确的造血器官，其中一群多能干细胞样祖细胞通过来自该器官内不同细胞群体的信号组合得以维持。淋巴腺既是研究祖细胞维持所涉及信号机制的理想模型，也是在高度保守的造血过程中鉴定新型调控机制的工具。在此，我们证明了TEAD转录因子扇贝型在造血祖细胞的维持和增殖中是必需的。我们鉴定了早期淋巴腺中一群由Hand、扇贝型和PVR配体PVF2表达所界定的新型血细胞。在这个独特的群体中，我们表明扇贝型维持PVF2的表达，而PVF2是血细胞增殖和达到正常淋巴腺大小所必需的。我们进一步证明，STAT信号标记早期淋巴腺中活跃增殖的血细胞，抑制该信号通路会导致淋巴腺生长减少，类似于扇贝型和PVF2缺失的情况，这表明PVR/STAT信号在调节淋巴腺大小中是必需的。最后，我们证明扇贝型调节PVR表达以及PVR/STAT/ADGF信号下游祖细胞的维持。这些发现进一步确立了TEAD家族转录因子在调节重要信号分子中的作用，并扩展了我们对调节淋巴腺稳态所需的祖细胞维持与增殖之间平衡的机制性认识。
