Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
Stem Cells Dev. 2013 Jan 1;22(1):58-72. doi: 10.1089/scd.2012.0074. Epub 2012 Aug 16.
Programmed cell death 2 (Pdcd2) is a highly conserved protein of undefined function, and is widely expressed in embryonic and adult tissues. The observations that knockout of Pdcd2 in the mouse is embryonic lethal at preimplantation stages, and that in Drosophila, Zfrp8, the ortholog of Pdcd2, is required for normal lymph gland development suggest that Pdcd2 is important for regulating hematopoietic development. Through genetic and functional studies, we investigated pdcd2 function during the zebrafish ontogeny. Knockdown of pdcd2 expression in zebrafish embryos resulted in defects in embryonic hematopoietic development. Loss of pdcd2 function caused increased expression of progenitor markers, and accumulation of erythroid progenitors during primitive hematopoiesis. Additionally, hematopoietic stem cells (HSCs) failed to appear in the aorta-gonad mesonephros, and were not able to terminally differentiate or reconstitute hematopoiesis. Pdcd2 effects on HSC emergence were cell autonomous and P53-independent, and loss of pdcd2 function was associated with mitotic defects and apoptosis. Restoration of runx1 function(s) and modulation of apoptosis through the inhibition of Jak/Stat signaling rescued the hematopoietic and erythroid defects resulting from pdcd2 knockdown. Our studies suggest that pdcd2 plays a critical role in regulating the transcriptional hierarchy controlling hematopoietic lineage determination. Furthermore, the effects of pdcd2 in regulating mitotic cell death may contribute to its role(s) in directing hematopoietic differentiation during development.
程序性细胞死亡蛋白 2（Pdcd2）是一种功能尚未明确的高度保守蛋白，广泛表达于胚胎和成年组织中。研究发现，敲除小鼠的 Pdcd2 会导致胚胎在着床前阶段死亡，而果蝇的 Zfrp8（Pdcd2 的同源物）对于正常的淋巴腺发育是必需的，这表明 Pdcd2 对于调控造血发育很重要。通过遗传和功能研究，我们调查了 Pdcd2 在斑马鱼胚胎发生过程中的功能。在斑马鱼胚胎中敲低 pdcd2 的表达会导致胚胎造血发育缺陷。Pdcd2 功能缺失导致祖细胞标记物的表达增加，并在原始造血过程中积累红系祖细胞。此外，造血干细胞（HSCs）未能出现在主动脉-性腺-中肾，并且无法进行终末分化或重建造血。Pdcd2 对 HSC 出现的影响是细胞自主的，与 P53 无关，Pdcd2 功能缺失与有丝分裂缺陷和细胞凋亡有关。恢复 runx1 的功能和通过抑制 Jak/Stat 信号转导来调节凋亡，可以挽救由 pdcd2 敲低引起的造血和红细胞缺陷。我们的研究表明，Pdcd2 在调控控制造血谱系决定的转录层次结构中起着关键作用。此外，Pdcd2 在调节有丝分裂细胞死亡中的作用可能有助于其在发育过程中指导造血分化的作用。
