Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

Abstract

The genetic basis of the development and variation of adult form of vertebrates is not well understood. To address this problem, we performed a mutant screen to identify genes essential for the formation of adult skeletal structures of the zebrafish. Here, we describe the phenotypic and molecular characterization of a set of mutants showing loss of adult structures of the dermal skeleton, such as the rays of the fins and the scales, as well as the pharyngeal teeth. The mutations represent adult-viable, loss of function alleles in the ectodysplasin (eda) and ectodysplasin receptor (edar) genes. These genes are frequently mutated in the human hereditary disease hypohidrotic ectodermal dysplasia (HED; OMIM 224900, 305100) that affects the development of integumentary appendages such as hair and teeth. We find mutations in zebrafish edar that affect similar residues as mutated in human cases of HED and show similar phenotypic consequences. eda and edar are not required for early zebrafish development, but are rather specific for the development of adult skeletal and dental structures. We find that the defects of the fins and scales are due to the role of Eda signaling in organizing epidermal cells into discrete signaling centers of the scale epidermal placode and fin fold. Our genetic analysis demonstrates dose-sensitive and organ-specific response to alteration in levels of Eda signaling. In addition, we show substantial buffering of the effect of loss of edar function in different genetic backgrounds, suggesting canalization of this developmental system. We uncover a previously unknown role of Eda signaling in teleosts and show conservation of the developmental mechanisms involved in the formation and variation of both integumentary appendages and limbs. Lastly, our findings point to the utility of adult genetic screens in the zebrafish in identifying essential developmental processes involved in human disease and in morphological evolution. A major goal of the study of developmental genetics is to understand the genes and developmental mechanisms underlying the formation of organismal complexity and diversity. Here, we focus on genes controlling postembryonic development and describe mutations in genes of the ectodysplasin (Eda) pathway in regulating the formation of the scales, skull, fins, and teeth. Mutations in genes of this signaling pathway are common in humans with defects in ectodermal structures such as hair, glands, and teeth. We show that the similar phenotypes of loss of Eda signaling in fish and human are due to a conserved early developmental stage in the development of mammalian hair and fish scales; subsequent development of these two structures diverge. Our findings show that the Eda signaling pathway has an ancestral role in regulating the developmental interactions involved in patterning and growth of the dermal skeleton of fish. Recent work has shown that these genes are associated with morphological variation between humans and evolution within fish populations, suggesting that alteration in the function of these genes permits viable morphological change. Our data support the value of forward genetic studies on postembryonic development to reveal the genetic and developmental basis of both human disease and morphological evolution.