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

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.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 neurona...

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

“…Recently, the Group C Sox gene, Sox11, has also been shown to influence craniofacial development. Mice lacking Sox11 frequently showed unilateral and bilateral orofacial clefts that were similar to phenotypes observed with certain Tcfap2a mutations (Sock et al, 2004;W. Feng and T. Williams, unpublished data).…”

“…Several members of the Sox gene family are required for face and limb development, particularly for skeletogenesis, and so represented important potential candidates for Tcfap2a regulation in these structures (Nakashima and de Crombrugghe, 2003;Richman and Lee, 2003;Sock et al, 2004). To determine whether Sox factors are indeed capable of interacting with this element, we generated full-length L-Sox5, Sox6, Sox8, and Sox9 proteins by in vitro transcription and translation.…”

“…Several Sox factors are known to play critical roles in craniofacial and limb skeletogenesis and are good candidates to regulate Tcfap2a (Bi et al, 1999(Bi et al, , 2001Smits et al, 2001;Sock et al, 2004). The Group E factor, Sox9, is an enticing candidate, given both its role in chondrogenesis and its responsiveness to retinoic acid (Bi et al, 1999(Bi et al, , 2001Sekiya et al, 2000;Akiyama et al, 2002Akiyama et al, , 2004MoriAkiyama et al, 2003;Sahar et al, 2005), an agent known to alter AP-2␣ expression in vitro and in vivo (Williams et al, 1988;Lü scher et al, 1989;Philipp et al, 1994;Shen et al, 1997).…”

Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms

“…9,10 The SOX gene family encodes a group of transcription factors that have critical roles in the determination of cell fate and differentiation. [9][10][11] Evidence suggests that SOX11 is critical for embryonic neurogenesis and tissue remodeling. 8,11,12 However, the data on the roles of SOX genes in hematopoiesis are very limited.…”

“…[9][10][11] Evidence suggests that SOX11 is critical for embryonic neurogenesis and tissue remodeling. 8,11,12 However, the data on the roles of SOX genes in hematopoiesis are very limited. To date, SOX4 is the only gene in the family that has been found to have an important role in the early B-and T-cell development.…”