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EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS

Hoxb1 Controls Cell Fate Specification and Proliferative Capacity of Neural Stem and Progenitor Cells

Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Key Words. Embryonic stem cells • Directed differentiation • Neural stem cells • Neural progenitors • Posterior identity • Microarray gene expression profiling • Gene regulation • Neural progenitor proliferation

Correspondence: Correspondence: Anthony Gavalas, Ph.D., Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens 11527, Greece. Telephone: 0030-210-6597209; Fax: 0030-210-6597545; e-mail: agavalas{at}bioacademy.gr

Received on February 25, 2008; accepted for publication on May 9, 2008.

First published online in STEM CELLS EXPRESS  May 22, 2008.

The directed differentiation of embryonic stem cells (ESCs) into neural stem cells (NSCs) of specific identities and the identification of endogenous pathways that may mediate expansion of NSCs are fundamental goals for the treatment of degenerative disorders and trauma of the nervous system. We report that timely induction of a Hoxb1 transgene in ESC-derived NSCs resulted in the specification of NSCs toward a hindbrain-specific identity through the activation of a rhombomere 4-specific genetic program and the repression of anterior neural identity. This change was accompanied by changes in signaling pathways that pattern the dorsoventral (DV) axis of the nervous system and concomitant changes in the expression of DV neural progenitor markers. Furthermore, Hoxb1 mediated the maintenance and expansion of posterior neural progenitor cells. Hoxb1⁺ cells kept proliferating upon mitogen withdrawal and became transiently amplifying progenitors instead of terminally differentiating. This was partially attributed to Hoxb1-dependent activation of the Notch signaling pathway and Notch-dependent STAT3 phosphorylation at Ser 727, thus linking Hox gene function with maintenance of active Notch signaling and the JAK/STAT pathway. Thus, timely expression of specific Hox genes could be used to establish NSCs and neural progenitors of distinct posterior identities. ESC-derived NSCs have a mixed DV identity that is subject to regulation by Hox genes. Finally, these findings set the stage for the elucidation of molecular pathways involved in the expansion of posterior NSCs and neural progenitors.

Disclosure of potential conflicts of interest is found at the end of this article.