or indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes. DNA binding (xenobiotic response element – XRE) The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3' within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3' in the promoter region of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5'-GTG-3' and AhR binding 5'-TC/TGC-3'. Recent research suggests that a second type of element termed AHRE-II, 5'-CATG(N6)C[T/A]TG-3', is capable of indirectly acting with the AhR/ARNT complex. Regardless of the response element, the result is a variety of differential changes in gene expression. Functional role in physiology and toxicology Role in development In terms of evolution, the oldest physiological role of AhR is in development. AhR is presumed to have evolved from invertebrates where it served a ligand-independent role in normal development processes. The AhR homolog in Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg. Ss dimerizes with tango (tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. Evolution of the receptor in vertebrates resulted in the ability to bind ligand and might have helped humans evolve to tolerate smoke of fires. In developing vertebrates, AhR seemingly plays a role in cellular proliferation and differentiation. Despite lacking a clear endogenous ligand, AhR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis, lymphoid systems, T-cells, neurons, and hepatocytes. AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion and is involved in megakaryocyte differentiation. In adulthood, signaling is associated with the stress response and mutations in AhR are associated with major depressive disorder. Adaptive and innate response The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway. The search for other metabolizing genes induced by AhR ligands, due to the presence of DREs, has led to the identification of an "AhR gene battery" of Phase I and Phase