Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.
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.
Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
Samantha D
SD
McElyea
Department of Orthodontics and Facial Genetics, Indiana University School of Dentistry, 1121 W. Michigan Street, DS 250B, Indianapolis, IN 46202, USA.|Department of Anthropology, University of Central Florida, 4000 Central Florida Blvd., Howard Phillips Hall, Room 309F, Orlando, FL 32816, USA
John M
JM
Starbuck
Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
Danika M
DM
Tumbleson-Brink
Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
Emily
E
Harrington
Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
Joshua D
JD
Blazek
Department of Orthodontics and Facial Genetics, Indiana University School of Dentistry, 1121 W. Michigan Street, DS 250B, Indianapolis, IN 46202, USA.
Ahmed
A
Ghoneima
Department of Orthodontics and Facial Genetics, Indiana University School of Dentistry, 1121 W. Michigan Street, DS 250B, Indianapolis, IN 46202, USA.
Katherine
K
Kula
Department of Biology, Indiana University-Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
Randall J
RJ
Roper
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019465:Craniofacial Abnormalities / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D005260:Female; D018628:Gene Dosage; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000097603:Dyrk Kinases
D002392:Catechin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C045651:epigallocatechin gallate