The aryl hydrocarbon receptor-signaling pathway and tissue remodeling: insights from the zebrafish (Danio rerio) model system.

Wound healing and regeneration are complex processes involving cellular differentiation and migration, cell-cell interactions, and coordinated matrix remodeling. Although most animals have the ability to repair an epidermal lesion, complete appendage regeneration is limited to teleost fish and several aquatic amphibians. Limb regeneration in adult mammals is only found in rare cases, such as deer antlers and rabbit ear cartilage (Goss, 1991). Epimorphic regeneration, the process that results in the functional reconstruction of the lost appendage, requires not only the regulation of cell proliferation and migration but also the recapitulation of the limb pattern. This process begins with the formation of a blastema, a mass of heterogeneous mesenchymal-like cells, between the appendage stump and the wounded epidermis (reviewed in Akimenko et al., 2003). Formation of the blastema is necessary for the regenerative process; however, the molecular mechanisms mediating blastema generation are still unclear. Recent data indicate that fibroblast growth factor (FGF) signaling is necessary for blastema formation (Lee et al., 2005; Poss et al., 2000b) and that members of the wnt signaling family are also involved (Poss et al., 2000a). Growth and elongation of the blastema occurs in an organized manner with the cells proximal to the blastema proliferating at a higher rate than those epithelial cells found distal (Santamaria et al., 1996). Several gene families are implicated in cell-cycle regulation in the regenerating tissue, including msxb, FGF, and the homeodomain proteins hoxd11 and hoxd12 (Akimenko et al., 2003). Finally, in order for the appendage regrowth to result in a functional duplicate of the lost limb, the pattern of the limb must be maintained, which is regulated by the expression of a variety of proteins including the transcription factor evx1 (Borday et al., 2001) as well as the coordinated action of sonic hedgehog (shh), bone morphogenic protein 2b (bmp2b), and patched (ptc) (Borday et al., 2001). In this issue of Toxicological Sciences, Andreasen et al. continue investigations into the effect of 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) on epimorphic regeneration using the zebrafish caudal fin model. Exposure to TCDD and related compounds results in a variety of lesions in mammals, including alterations in liver function and lipid metabolism, weight loss, immune system suppression, endocrine and nervous system dysfunction, as well as severe skin lesions (Mukerjee, 1998). Although the exact mechanism underlying TCDD-mediated pathologies is not completely elucidated, it is accepted that TCDDmediates the majority of these effects through activation of the aryl hydrocarbon receptor (AhR)–signaling pathway. The AhR and its dimerization partner Arnt (AhR nuclear translocator) are members of the basic Helix-Loop-Helix PerArnt-Sim domain family of transcription factors that have diverse biological roles ranging from developmental regulation to environmental sensing (Crews and Fan, 1999). Members of the zebrafish AhR pathway have been characterized including two orthologs of mammalian AhR (zfAhR1 and zfAhR2) and two Arnt orthologs (zfArnt1 and zfArnt2). Data indicate that zfAhR2 and zfArnt1 are functional homologs for the mammalian AhR and Arnt (reviewed in Carney et al., 2006). The work reported by Andreason and colleagues may link to the function of TCDD and the AhR pathway in tissue development and morphogenesis in mammalian development. This process requires similar processes as observed in epimorphic regeneration, including changes in cell proliferation, directional migration, matrix metabolism and deposition, and pattern formation. Data from mammalian systems suggest that TCDD affects processes critical to embryonic development. For example, postnatal development of the seminal vesicles, including vesicle branching and differentiation, is reduced in rats exposed to TCDD in utero (Hamm et al., 2000). Further, aberrant mammary development, characterized by decreased tubule branching, is observed in rats exposed to TCDD (Brown and Lamartiniere, 1995). Mice exposed to TCDD in utero develop cleft palate, which is thought to result from insufficient differentiation of the epithelial cells of the palatal shelves (Abbott and Birnbaum, 1989; Takagi et al., 2000). These 1 To whom correspondence should be addressed at Department of Biochemistry and Microbiology, 76 Lipman Drive, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Fax: (732) 932-8965. E-mail: lawhite@aesop.rutgers.edu.