SOX9 is required for maintenance of the pancreatic progenitor cell pool

doi:10.1073/pnas.0609217104

SOX9 is required for maintenance of the pancreatic progenitor cell pool

*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300;
^†The Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262;
^‡Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne NE1 3BZ, United Kingdom; and
^§Institute of Human Genetics and Anthropology, University of Freiburg, D-79106 Freiburg, Germany

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 11, 2006 (received for review October 18, 2006)

Abstract

The factors necessary to maintain organ-specific progenitor cells are poorly understood and yet of extreme clinical importance. Here, we identify the transcription factor SOX9 as the first specific marker and maintenance factor of multipotential progenitors during pancreas organogenesis. In the developing pancreas, SOX9 expression is restricted to a mitotically active, Notch-responsive subset of PDX1⁺ pluripotent progenitors and is absent from committed endocrine precursors or differentiated cells. Similar to Notch mutations, organ-specific Sox9 inactivation in mice causes severe pancreatic hypoplasia resulting from depletion of the progenitor cell pool. We show that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state. Our finding that SOX9 regulates the Notch-effector HES1 suggests a Notch-dependent mechanism and establishes a possible genetic link between SOX factors and Notch. These findings will be of major significance for the development of in vitro protocols for cell replacement therapies.

Footnotes

^¶To whom correspondence should be addressed. E-mail: msander{at}uci.edu
Author contributions: P.A.S. and M.S. designed research; P.A.S., K.K.F., M.N.T., and E.E.M. performed research; J.J., R.K., and G.S. contributed new reagents/analytic tools; P.A.S., K.K.F., M.N.T., and M.S. analyzed data; and P.A.S. and M.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains suppoting information online at www.pnas.org/cgi/content/full/0609217104/DC1.
Abbreviation:

E,

embryonic day.