Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling.
Journal: 2004/August - Molecular and Cellular Biology
ISSN: 0270-7306
Abstract:
The high-mobility-group domain-containing transcription factor Sox11 is expressed transiently during embryonic development in many tissues that undergo inductive remodeling. Here we have analyzed the function of Sox11 by gene deletion in the mouse. Sox11-deficient mice died at birth from congenital cyanosis, likely resulting from heart defects. These included ventricular septation defects and outflow tract malformations that ranged from arterial common trunk to a condition known as double outlet right ventricle. Many other organs that normally express Sox11 also exhibited severe developmental defects. We observed various craniofacial and skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Eyelids and the abdominal wall did not close properly in some Sox11-deficient mice. This phenotype suggests a prime function for Sox11 in tissue remodeling and identifies SOX11 as a potentially mutated gene in corresponding human malformation syndromes.
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Mol Cell Biol 24(15): 6635-6644

Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling

Institut für Biochemie, Institut für Anatomie, Universität Erlangen-Nürnberg, Erlangen, Max-Planck-Institut für Neurobiologie, Martinsried, Germany2
Corresponding author. Mailing address: Institut für Biochemie, Fahrstrasse 17, D-91054 Erlangen, Germany. Phone: 49 9131 85 24620. Fax: 49 9131 85 22484. E-mail: ed.negnalre-inu.mehcoib@rengew.m.
Received 2004 Mar 10; Revised 2004 Apr 24; Accepted 2004 May 11.

Abstract

The high-mobility-group domain-containing transcription factor Sox11 is expressed transiently during embryonic development in many tissues that undergo inductive remodeling. Here we have analyzed the function of Sox11 by gene deletion in the mouse. Sox11-deficient mice died at birth from congenital cyanosis, likely resulting from heart defects. These included ventricular septation defects and outflow tract malformations that ranged from arterial common trunk to a condition known as double outlet right ventricle. Many other organs that normally express Sox11 also exhibited severe developmental defects. We observed various craniofacial and skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Eyelids and the abdominal wall did not close properly in some Sox11-deficient mice. This phenotype suggests a prime function for Sox11 in tissue remodeling and identifies SOX11 as a potentially mutated gene in corresponding human malformation syndromes.

Abstract

Transcription factors of the Sox protein family are characterized by the possession of a subtype of high-mobility-group domain which allows sequence-specific binding to the minor groove of DNA (31). This domain was first identified in Sry, the prototypic family member involved in male sex determination. Over the last few years, many Sox proteins have been shown to be involved as regulators in diverse developmental processes ranging from epiblast formation to the terminal differentiation of certain cell types (3, 31).

The 20 Sox proteins which have been identified in mammals can be further subdivided into eight groups (groups A to H) according to their degrees of similarity both within and outside the high-mobility-group domain. Mammalian group C, for instance, consists of the three highly related proteins Sox4, Sox11, and Sox22. Sox4 has been studied extensively in vivo and has been shown to be essential for pro-B-cell expansion and for the formation of semilunar valves and of the outflow tract from the endocardial ridges of the heart (25). Further nonessential roles for Sox4 have been defined in thymocyte differentiation (24).

Much less is known about the biological role of Sox11 and Sox22. Species in which Sox11 has been identified include humans, mice, rats, chickens, Xenopus laevis, and zebra fish (11, 14, 15, 17, 21, 22, 30). Sox11 functions as a strong transcriptional activator in tissue culture systems and possesses a transactivation domain at its extreme carboxy terminus with a high level of homology to the corresponding region of Sox4 (17).

The expression of Sox11 has also been studied in several species. In zebra fish, in which two Sox11 orthologs exist because of the recent whole-genome duplication in teleosts, Sox11 transcripts are maternally inherited (22). In all species analyzed, Sox11 is present during gastrulation and early postgastrulation development throughout the embryo, with the notable exception of the heart (14, 17, 22). Later during development, Sox11 is prominently expressed in the developing nervous system in both glial and neuronal lineages and at many sites throughout the embryo where epithelial-mesenchymal interactions occur (14, 17, 30). At sites of such epithelial-mesenchymal interactions, Sox11 can be found in the mesenchymal or epithelial compartment, and it has been postulated to be involved in inductive remodeling (14). Its expression quite often exhibits a dynamic pattern with regards to both expression sites and expression levels. In several tissues, Sox11 exhibits an expression profile that is very similar to that of the highly related Sox4 protein (7, 17), whereas in other tissues, the occurrence of both proteins is complementary (18). Sox11 expression in most tissues is transient. As a consequence, there is little Sox11 expression in the adult, in contrast to its widespread occurrence during embryogenesis. Here we have started to study the role of Sox11 during mouse development by generating a Sox11-deficient mouse model. This model yields important insights into the biological role of Sox11.

Acknowledgments

We thank Gertrud Link and Elke Kretzschmar for expert technical assistance.

This work was funded by a Fonds der Chemischen Industrie grant to M.W.

Acknowledgments

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