Comparative Biochemistry and Physiology Part B 126 (2000) 199 – 211 Metamorphosis Dual functions of thyroid hormone receptors during Xenopus development  Laurent M. Sachs a , Sashko Damjanovski a , Peter L. Jones a , Qing Li a , Tosikazu Amano a , Shuichi Ueda b , Yun-Bo Shi a, *, Atsuko Ishizuya-Oka b a Laboratory of Molecular Embryology, National Institute of Child Health and Human De6elopment, National Institutes of Health, Bethesda, MD 20892 -5431, USA b Department of Histology and Neurobiology, Dokkyo Uni6ersity School of Medicine, Mibu, Tochigi 321 -02, Japan Received 18 August 1999; received in revised form 16 November 1999; accepted 18 November 1999 Abstract Thyroid hormone (TH) plays a causative role in anuran metamorphosis. This effect is presumed to be manifested through the regulation of gene expression by TH receptors (TRs). TRs can act as both activators and repressors of a TH-inducible gene depending upon the presence and absence of TH, respectively. We have been investigating the roles of TRs during Xenopus lae6is development, including premetamorphic and metamorphosing stages. In this review, we summarize some of the studies on the TRs by others and us. These studies reveal that TRs have dual functions in frog development as reflected in the following two aspects. First, TRs function initially as repressors of TH-inducible genes in premetamorphic tadpoles to prevent precocious metamorphosis, thus ensuring a proper period of tadpole growth, and later as activators of these genes to activate the metamorphic process. Second, TRs can promote both cell proliferation and apoptosis during metamorphosis, depending upon the cell type in which they are expressed. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Apoptosis; Cell death; Cell proliferation; Metamorphosis; Transcriptional regulation; Xenopus lae6is ; Amphibian; Thyroid hormone receptor www.elsevier.com/locate/cbpb 1. Introduction Thyroid hormone (TH) influences diverse bio- logical processes (Hetzel, 1989; Mandel et al., 1993). In adult mammals, TH regulates the physi- ological function of many organs (Guernsey and Edelman, 1983; Freake and Oppenheimer, 1995; Silva, 1995). In humans, inappropriate levels of TH lead to various diseases. In addition, TH also plays important roles during embryogenesis and organogenesis. Since early part of this century, hypothyroidism has been known to cause severe developmental defects in humans, most notably human cretinism, a form of defect characterized by mental retardation and short stature due to deficiencies in brain and skeletal development (Dussault and Ruel, 1987; Hetzel, 1989; Mandel et al., 1993; Porterfield and Hendrich, 1993). Compared to other vertebrates, anuran devel- opment is perhaps the most dependent on TH. Anuran development takes place in two phases. Its embryogenesis occurs prior to the formation of  Presented at the International Symposium ‘‘The Frontiers of the Biology of Amphibia’’, Hiroshima, Japan, March 22 – 24, 1999. * Corresponding author. Tel.: +1-301-4021004; fax: +1- 301-4021323. E-mail address: shi@helix.nih.gov (Y.-B. Shi) 0305-0491/00/$ - see front matter © 2000 Elsevier Science Inc. All rights reserved. PII:S0305-0491(00)00198-X