Intrinsic transition of embryonic stem-cell differentiation into neural progenitors

• Published in: Nature (London) Vol. 470; no. 7335; pp. 503 - 509
• Main Authors: Kamiya, Daisuke, Banno, Satoe, Sasai, Noriaki, Ohgushi, Masatoshi, Inomata, Hidehiko, Watanabe, Kiichi, Kawada, Masako, Yakura, Rieko, Kiyonari, Hiroshi, Nakao, Kazuki, Jakt, Lars Martin, Nishikawa, Shin-ichi, Sasai, Yoshiki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2011; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Bone Morphogenetic Protein 4 - deficiency; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Cadherins - metabolism; Cell Differentiation; Cell Lineage; Cells, Cultured; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryology: invertebrates and vertebrates. Teratology; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Developmental - genetics; Genetic aspects; Germ Layers - cytology; Germ Layers - embryology; Germ Layers - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Mice; Models, Biological; multidisciplinary; Neural Plate - cytology; Neural Plate - embryology; Neural Plate - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurons; Oligonucleotide Array Sequence Analysis; Organogenesis. Fetal development; Organogenesis. Physiological fonctions; p300-CBP Transcription Factors - metabolism; Proteins; Science; Science (multidisciplinary); SOXB1 Transcription Factors - metabolism; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Xenopus; United States; Embryonic development; Vertebrata; Mammalia; Mouse; Stem cell; Rodentia; Nervous system; Cell differentiation; Gene expression
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09726

The neural fate is generally considered to be the intrinsic direction of embryonic stem (ES) cell differentiation. However, little is known about the intracellular mechanism that leads undifferentiated cells to adopt the neural fate in the absence of extrinsic inductive signals. Here we show that the zinc-finger nuclear protein Zfp521 is essential and sufficient for driving the intrinsic neural differentiation of mouse ES cells. In the absence of the neural differentiation inhibitor BMP4, strong Zfp521 expression is intrinsically induced in differentiating ES cells. Forced expression of Zfp521 enables the neural conversion of ES cells even in the presence of BMP4. Conversely, in differentiation culture, Zfp521-depleted ES cells do not undergo neural conversion but tend to halt at the epiblast state. Zfp521 directly activates early neural genes by working with the co-activator p300. Thus, the transition of ES cell differentiation from the epiblast state into neuroectodermal progenitors specifically depends on the cell-intrinsic expression and activator function of Zfp521. The neural default in the embryo Embryonic stem cells have the potential to develop into any cell type in the body, but in culture, their default pathway is to differentiate into neural cells. Little is known about the mechanism that seals the neural fate in the absence of extrinsic induction signals. Now, a cell-intrinsic factor has been identified as the driver of this 'neural default' phenomenon in the early embryo: the zinc-finger nuclear protein Zfp521 is shown to be necessary and sufficient to force a neural fate. This work furthers our understanding of embryo development and has implications for regenerative medicine and drug discovery. Embryonic stem cells are typically driven to adopt a neural fate in response to inductive signals originating from the environment. However, little is known regarding the downstream molecular mechanisms operating intracellularly to induce this transformation and differentiation. Here, the zinc-finger nuclear protein Zfp521 is demonstrated to be necessary and sufficient to force a neural fate, providing evidence for a cell-intrinsic factor important in transitioning multipotent ES cells to a neural fate.