Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

Samantha D Mcelyea,Danika M Tumbleson-Brink,Ahmed Ghoneima,Joshua D Blazek,Emily Harrington,John M Starbuck,Katherine Kula,Randall J Roper

doi:10.1093/hmg/ddw309

Abstract

Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene–phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

Highlights

Down syndrome (DS, OMIM 190685) affects 140 of 100 000 live births, and all humans with DS exhibit dysmorphic craniofacial phenotypes and impaired cognition
Dysregulation of Dyrk1a and Regulator of Calcineurin 1 (Rcan1) have been hypothesized to influence craniofacial phenotypes associated with DS [20], and we hypothesized that these trisomic genes may be involved in the neural crest cell (NCC) deficit of E9.5 Ts65Dn embryos [18]
Before the NCC deficit is established in trisomic embryos at E9.25 (15–19 somites), trisomic embryos displayed decreased expression of Dyrk1a RNA and increased Rcan1 RNA expression in both the E9.25 PA1 and neural tube (NT) (Fig. 1A)

Summary

Introduction

Down syndrome (DS, OMIM 190685) affects 140 of 100 000 live births, and all humans with DS exhibit dysmorphic craniofacial phenotypes and impaired cognition. During prenatal morphogenesis and growth, individuals with Trisomy 21 (Ts21) develop craniofacial abnormalities including reduced maxillary length, altered frontomaxillary facial angles and short, broad heads [1,2,3,4]. These developmental craniofacial differences preface those seen in newborn, children and adult humans with DS including midface hypoplasia, a small oral cavity, brachycephaly and a generalized reduction in facial dimensions due to decreased growth rates and increased fluctuating asymmetry of facial soft tissues associated with decreased developmental homeostasis [4,5,6,7,8]. Adult Ts65Dn mice exhibit increased neurocranial widths (i.e. brachycephaly), a flattened occiput and an overall reduction in size of much of the craniofacial skeleton; including the midface, maxilla, mandible, facial height and interorbital breadth [7]

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Results

Conclusion