Border formation in a Bmp gradient reduced to single dissociated cells

*Department of Pathology and Laboratory Medicine, School of Medicine, University of California, D440 Medical Sciences I, Irvine, CA 92697-4800;
^†Department of Developmental and Cell Biology, School of Biological Sciences, University of California, 5205 McGaugh Hall, Irvine, CA 92697-2300; and
^‡Unité de Génétique Moléculaire de la Morphogenése, Institut Pasteur, Unité de Recherche Associée 2578, Centre National de la Recherche Scientifique, 25, Rue du Dr. Roux, 75724 Paris Cedex 15, France

Edited by John B. Gurdon, University of Cambridge, Cambridge, United Kingdom, and approved January 6, 2008 (received for review September 26, 2007)

Abstract

Conversions of signaling gradients into sharp “all-or-none” borders are fundamental to tissue and organismal development. However, whether such conversions can be meaningfully reduced to dissociated cells in culture has been uncertain. Here we describe ultrasensitivity, the phenomenon equivalent to an all-or-none response, in dissociated neural precursor cells (NPCs) exposed to bone morphogenetic protein 4 (Bmp4). NPC ultrasensitivity is evident at the population and single-cell levels based on Msx1 induction, a well known Bmp target response, and occurs in the context of gene expression changes consistent with Bmp4 activity as a morphogen. Dissociated NPCs also display immediate early kinetics and irreversibility for Msx1 induction after brief Bmp4 exposure, which are attractive features for initial border formation. Relevance to border formation in vivo is provided by Bmp4 gain-of-function studies in explants and evidence for single-cell ultrasensitivity in normal and mutant Bmp gradient contexts in the developing forebrain. Together, these studies demonstrate relatively simple, robust, and reducible cell-intrinsic properties that contribute to developmental border formation within a signaling gradient.

Footnotes

^§To whom correspondence should be addressed. E-mail: emonuki{at}uci.edu
Author contributions: J.S.H., L.T.D., D.S.C., and E.S.M. designed research; J.S.H., L.T.D., D.S.C., M.P., J.Y.R., and R.S. performed research; B.R. contributed new reagents/analytic tools; J.S.H., L.T.D., D.S.C., and E.S.M. analyzed data; and J.S.H. and E.S.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709100105/DC1.