QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McFadden, D. G. Articles by Olson, E. N. Search for Related Content PubMed PubMed Citation Articles by McFadden, D. G. Articles by Olson, E. N. Social Bookmarking                         What's this?

Misexpression of dHAND induces ectopic digits in the developing limb bud in the absence of direct DNA binding

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148, USA
² Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148, USA
³ Department of Cell Biology and Genetics, Erasmus University Rotterdam, Dr Molewaterplein 50, 3015GE, Rotterdam, The Netherlands

*Author for correspondence (e-mail: eolson{at}hamon.swmed.edu)

Accepted 5 April 2002

Basic helix-loop-helix (bHLH) transcription factors control developmental decisions in a wide range of embryonic cell types. The HLH motif mediates homo- and heterodimerization, which juxtaposes the basic regions within the dimeric complex to form a bipartite DNA binding domain that recognizes a DNA consensus sequence known as an E-box. eHAND and dHAND (also known as HAND1 and HAND2) are closely related bHLH proteins that control cardiac, craniofacial and limb development. Within the developing limb, dHAND expression encompasses the zone of polarizing activity in the posterior region, where it has been shown to be necessary and sufficient to induce the expression of the morphogen sonic hedgehog. Misexpression of dHAND in the anterior compartment of the limb bud induces ectopic expression of sonic hedgehog, with resulting preaxial polydactyly and mirror image duplications of posterior digits. To investigate the potential transcriptional mechanisms involved in limb patterning by dHAND, we have performed a structure-function analysis of the protein in cultured cells and ectopically expressed dHAND mutant proteins in the developing limbs of transgenic mice. We show that an N-terminal transcriptional activation domain, and the bHLH region, are required for E-box-dependent transcription in vitro. Remarkably, however, digit duplication by dHAND requires neither the transcriptional activation domain nor the basic region, but only the HLH motif. eHAND has a similar limb patterning activity to dHAND in these misexpression experiments, indicating a conserved function of the HLH regions of these proteins. These findings suggest that dHAND may act via novel transcriptional mechanisms mediated by protein-protein interactions independent of direct DNA binding.

Key words: dHAND/HAND2, Limb, Zone of polarizing activity, Sonic hedgehog, DNA binding, Basic helix-loop-helix, Mouse

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. C. Butterfield, V. Metzis, E. McGlinn, S. J. Bruce, B. J. Wainwright, and C. Wicking Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb Development, October 15, 2009; 136(20): 3515 - 3524. [Abstract] [Full Text] [PDF]

				S. M. Reamon-Buettner, Y. Ciribilli, I. Traverso, B. Kuhls, A. Inga, and J. Borlak A functional genetic study identifies HAND1 mutations in septation defects of the human heart Hum. Mol. Genet., October 1, 2009; 18(19): 3567 - 3578. [Abstract] [Full Text] [PDF]

				N. Liu, A. C. Barbosa, S. L. Chapman, S. Bezprozvannaya, X. Qi, J. A. Richardson, H. Yanagisawa, and E. N. Olson DNA binding-dependent and -independent functions of the Hand2 transcription factor during mouse embryogenesis Development, March 15, 2009; 136(6): 933 - 942. [Abstract] [Full Text] [PDF]

				N. Funato, S. L. Chapman, M. D. McKee, H. Funato, J. A. Morris, J. M. Shelton, J. A. Richardson, and H. Yanagisawa Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2 Development, February 15, 2009; 136(4): 615 - 625. [Abstract] [Full Text] [PDF]

				M. T. Kassouf, H. Chagraoui, P. Vyas, and C. Porcher Differential use of SCL/TAL-1 DNA-binding domain in developmental hematopoiesis Blood, August 15, 2008; 112(4): 1056 - 1067. [Abstract] [Full Text] [PDF]

				J. M. Brito, M.-A. Teillet, and N. M. Le Douarin Induction of mirror-image supernumerary jaws in chicken mandibular mesenchyme by Sonic Hedgehog-producing cells Development, July 1, 2008; 135(13): 2311 - 2319. [Abstract] [Full Text] [PDF]

				B. A. Firulli, B. A. Redick, S. J. Conway, and A. B. Firulli Mutations within Helix I of Twist1 Result in Distinct Limb Defects and Variation of DNA Binding Affinities J. Biol. Chem., September 14, 2007; 282(37): 27536 - 27546. [Abstract] [Full Text] [PDF]

				M. E. Lucas, F. Muller, R. Rudiger, P. D. Henion, and H. Rohrer The bHLH transcription factor hand2 is essential for noradrenergic differentiation of sympathetic neurons Development, October 15, 2006; 133(20): 4015 - 4024. [Abstract] [Full Text] [PDF]

				D. Skowronska-Krawczyk, L. Matter-Sadzinski, M. Ballivet, and J.-M. Matter The Basic Domain of ATH5 Mediates Neuron-Specific Promoter Activity during Retina Development Mol. Cell. Biol., November 15, 2005; 25(22): 10029 - 10039. [Abstract] [Full Text] [PDF]

				S. Morin, G. Pozzulo, L. Robitaille, J. Cross, and M. Nemer MEF2-dependent Recruitment of the HAND1 Transcription Factor Results in Synergistic Activation of Target Promoters J. Biol. Chem., September 16, 2005; 280(37): 32272 - 32278. [Abstract] [Full Text] [PDF]

				A. A. Hill and P. R. Riley Differential Regulation of Hand1 Homodimer and Hand1-E12 Heterodimer Activity by the Cofactor FHL2 Mol. Cell. Biol., November 15, 2004; 24(22): 9835 - 9847. [Abstract] [Full Text] [PDF]

				L.-B. Ruest, X. Xiang, K.-C. Lim, G. Levi, and D. E. Clouthier Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity Development, September 15, 2004; 131(18): 4413 - 4423. [Abstract] [Full Text] [PDF]

				Y. Morikawa and P. Cserjesi Extra-embryonic vasculature development is regulated by the transcription factor HAND1 Development, May 1, 2004; 131(9): 2195 - 2204. [Abstract] [Full Text] [PDF]

				J. L. Rychlik, V. Gerbasi, and E. J. Lewis The Interaction between dHAND and Arix at the Dopamine {beta}-Hydroxylase Promoter Region Is Independent of Direct dHAND Binding to DNA J. Biol. Chem., December 5, 2003; 278(49): 49652 - 49660. [Abstract] [Full Text] [PDF]

				S. Azmi, H. Sun, A. Ozog, and R. Taneja mSharp-1/DEC2, a Basic Helix-Loop-Helix Protein Functions as a Transcriptional Repressor of E Box Activity and Stra13 Expression J. Biol. Chem., May 23, 2003; 278(22): 20098 - 20109. [Abstract] [Full Text] [PDF]

				H. Yanagisawa, D. E. Clouthier, J. A. Richardson, J. Charite, and E. N. Olson Targeted deletion of a branchial arch-specific enhancer reveals a role of dHAND in craniofacial development Development, March 15, 2003; 130(6): 1069 - 1078. [Abstract] [Full Text] [PDF]

				M. A. Ros, R. D. Dahn, M. Fernandez-Teran, K. Rashka, N. C. Caruccio, S. M. Hasso, J. J. Bitgood, J. J. Lancman, and J. F. Fallon The chick oligozeugodactyly (ozd) mutant lacks sonic hedgehog function in the limb Development, February 1, 2003; 130(3): 527 - 537. [Abstract] [Full Text] [PDF]