Growth factor signaling alters the morphology of the zebrafish ethmoid plate

Abstract

Craniofacial development relies on coordinated tissue interactions that allow for patterning and growth of the face. We know a priori that the Wingless, fibroblast growth factor, Hedgehog and transforming growth factor-beta growth factor signaling pathways are required for the development of the face, but how they contribute to the shape of the face is largely untested. Here, we test how each signaling pathway contributes to the overall morphology of the zebrafish anterior neurocranium. We tested the contribution of each signaling pathway to the development of the ethmoid plate during three distinct time periods: the time of neural crest migration [10 hour post fertilization (hpf)]; once the neural crest is resident in the face (20 hpf); and finally at the time at which the cartilaginous condensations are being initiated (48 hpf). Using geometric morphometric analysis, we conclude that each signaling pathway contributes to the shape, size and morphology of the ethmoid plate in a dose-, and time-dependent fashion.

Optimization of the TeraTox Assay for Preclinical Teratogenicity Assessment

“…This compound panel consisted of both commercial and developmental pharmaceuticals with known teratogenicity potential (ie, positive or negative) available from either human data, as reported in FDA drug labels , or from in vivo EFD studies in rats and/or rabbits ( ICH, 2020 ). Some compounds without existing human or in vivo animal data were classified as teratogens based on a known teratogenic hazard associated with their mode of action ( Belair et al, 2020 ; Chen et al, 2002 ; Cusack et al, 2017 ; Evans, 2007 ; Kameoka et al, 2014 ; Lipinski et al, 2008 ; Sakata and Chen, 2011 ; Wang et al, 2013 ; Worley et al, 2018 ). Compounds that did not result in increased incidences of birth defects in an adequate prospective cohort study accepted by health authorities were considered as nonteratogenic in humans, at least at the therapeutically relevant exposure levels ( Adams et al, 1969 ; Daniel et al, 2019 ; Dashe and Gilstrap, 1997 ; Etwel et al, 2014 ; Muanda et al, 2017 ; Rumbold et al, 2015 ; Supplementary Table 2 ).…”

Optimization of the TeraTox assay for preclinical teratogenicity assessment

“…positive or negative) available from either human data, as reported in FDA drug labels, or from in vivo EFD studies in rats and/ or rabbits (ICH 2020). Some compounds without existing human or in vivo animal data were classified as teratogens based on a known teratogenic hazard associated with their mode of action (Belair et al 2020; Chen et al 2002; Cusack et al 2017; Evans 2007; Kameoka et al 2013; Lipinski et al 2008; Sakata and Chen 2011; Wang et al 2013; Worley et al 2018). Compounds that did not result in increased incidences of birth defects in an adequate prospective cohort study accepted by health authorities were considered as non-teratogenic in humans, at least at the therapeutically-relevant exposure levels (Adams et al 1969; Daniel et al 2019; Dashe and Gilstrap 1997; Etwel et al 2014; Muanda et al 2017; Rumbold et al 2015) (Suppl.…”

“…Compounds without existing human or in vivo animal data were classified as teratogens based on known teratogenic risks associated with their mode of action (18,(48)(49)(50)(51)(52)(53)(54)(55). Some compounds have been taken by cohorts of pregnant women and did not lead to any observed increase in the frequency of malformations during early pregnancy.…”

Cellular and molecular mechanisms in the development of a cleft lip and/or cleft palate; insights from zebrafish (Danio rerio)

“…This study confirmed that the above signaling pathways contribute to development of the mediolateral and proximal distal axis of the face and that small perturbations of growth factor signaling can alter the shape of the developing face. The most significant effect was found in early stages, such as 10 and 20 hpf (Cusack, Parsons, Weinberg, Vieira, & Szabo‐Rogers, 2017). Di I tracing of NCCs have shown that shh is a key regulator for upper jaw and ethmoid cartilage development in zebrafish and these findings were compatible with CLP where mutations of the Shh pathway resulted in different degrees of CLP development (Wada et al, 2005).…”