A zinc finger protein Zfp521 directs neural differentiation and beyond

Human embryonic stem (ES) cells offer tremendous opportunities for regenerative medicine, because they are capable of indefinite self-propagation and of differentiating into any cell types of three germ layers [1]. Significant progress has been made in understanding the maintenance of ES cells, and now induced pluripotent stem cells can be generated from most (if not all) somatic cells with the defined transcription factors c-MYC, KLF4, SOX2 and OCT4 [2] and/or small molecules [3]. A better understanding of how to derive specific cell types from stem cells will increase the rate of translation of basic laboratory work to the clinic for patient-tailored therapy.Formation of the central nervous system has drawn the attention of developmental biologists for almost a century since Spemann and Mangold discovered that the dorsal lip of the blastopore was capable of inducing neural differentiation in Xenopus gastrula [4]. A list of Spemann organizers has been identified that to date includes Noggin, Gremlin, Cerberus, Twisted Gastrulation and Chordin. They are secreted molecules that directly bind and antagonize bone morphogenetic proteins (BMPs) [5,6].BMPs bind/activate specific high-affinity type I and type II Ser/Thr kinase receptors, including ALK1 to ALK7, ActRII, ActRIIB, TβRII, BMPRI and BMPRII, and signal through the canonical SMAD pathways. BMP signaling pathways are present in ES cells and readily inhibit neural differentiation. When BMP inhibition is removed, the majority of surviving cells differentiate into neurons. Neural induction is therefore considered a default process that takes place autonomously and intrinsically [5]. Little is known, however, about the intracellular factors involved.Kamiya and colleagues now report in Nature, with compelling evidence, that a zinc finger (ZF) nuclear protein, Zfp521, is a key intrinsic molecule capable of directing ES cells to neural progenitors [7]. They first knocked-in a GFP reporter gene into a neural precursor loc