Thyroid hormone regulates abrupt skin morphogenesis during zebrafish postembryonic development

Abstract

Thyroid hormone is a key regulator of post-embryonic vertebrate development. Skin is a biomedically important thyroid hormone target organ, but the cellular and molecular mechanisms underlying skin pathologies associated with thyroid dysfunction remain obscure. The transparent skin of zebrafish is an accessible model system for studying vertebrate skin development. During post-embryonic development of the zebrafish, scales emerge in the skin from a hexagonally patterned array of dermal papillae, like other vertebrate skin appendages such as feathers and hair follicles. We show here that thyroid hormone regulates the rate of post-embryonic dermal development through interaction with nuclear hormone receptors. This couples skin development with body growth to generate a well ordered array of correctly proportioned scales. This work extends our knowledge of thyroid hormone actions on skin by providing in-vivo evidence that thyroid hormone regulates multiple aspects of dermal development.

Transcriptomic profiling of tissue environments critical for post-embryonic patterning and morphogenesis of zebrafish skin

“…We have shown that hypoTH fish lack superficial dermal cell types at the stage sampled for sequencing, though these cell types do appear later in development (Aman et al, 2021). To confirm the presence of residual, pre-SFC in eda mutants, we imaged live fish expressing ET37:EGFP, which enables visualization of all dermal cells (Parinov et al, 2004;Aman et al, 2021). Indeed, eda mutants exhibited a mat of ET37:EGFP+ dermal cells-presumptive pre-SFC-beneath the epidermis that was not present in hypoTH fish (Fig 3B).…”

“…Based on these findings, we predicted that hypodermis would be malformed or missing in live bnc2 mutants. To test this prediction and validate inferences from the single cell transcriptome data, we imaged the dermis of live animals expressing ET37:EGFP, expressed broadly across dermal cell types (Aman et al, 2021). In wild-type controls, the hypodermis appeared as a thin, nearly confluent cell layer deep in the dermis, whereas in bnc2 mutants no such layer was apparent, instead the deepest dermis appeared to contain only dermal mesenchyme (Fig 4D; Fig 4 S1A; Fig 1 S1B).…”

“…Skin is a large and complex organ system, with contributions from multiple embryonic germ layers and a variety of distinct cell types. Conveniently, pigment pattern formation and squamation occur simultaneously during post-embryonic development, in different layers of the skin (Fig 1B) (Aman et al, 2021). To capture individual transcriptomes from a minimally biased sampling of skin cells, we performed single nucleus combinatorial indexing (sci)-RNA-seq (Cao et al, 2017;Cao et al, 2019) on nuclei from pooled, fresh-frozen whole skins at 9.6 SSL, a key developmental stage during skin patterning and morphogenesis.…”

“…Since hypoTH basal cells at this stage fail to recruit dermal cells (Aman et al, 2021), we further hypothesized that ligands previously implicated in dermal cell migration would be enriched among hypoTH differentially expressed genes. Closer inspection of differentially expressed signaling ligand genes in basal epidermal cells showed that, indeed, TH promotes expression of pdgfaa, pdgfba, and wnt6b, which encode orthologs of signaling ligands known to recruit dermal cells to epidermis in amniotes (Fig 3H) (Karlsson et al, 1999;Chen et al, 2012).…”

“…Comparing developmental mechanisms across species can give insights into the origin and evolution of this important organ system and elucidate fundamental mechanisms of potential relevance to human dermatology. To this end, skin morphogenesis and patterning has been studied across a variety of organisms, yielding insights into both general and species-specific mechanisms (Duverger and Morasso, 2009;Chen et al, 2015;Patterson and Parichy, 2019;Aman and Parichy, 2020). Zebrafish (Danio rerio) is an outstanding organism for studying vertebrate skin patterning and morphogenesis.…”