Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper
{"title":"在唐氏综合征小鼠模型的发育过程中,出现与三体 Dyrk1a 相关的骨骼表型的性别特异性。","authors":"Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper","doi":"10.1242/dmm.050914","DOIUrl":null,"url":null,"abstract":"<p><p>Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449447/pdf/","citationCount":"0","resultStr":"{\"title\":\"Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.\",\"authors\":\"Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper\",\"doi\":\"10.1242/dmm.050914\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.</p>\",\"PeriodicalId\":11144,\"journal\":{\"name\":\"Disease Models & Mechanisms\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449447/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Disease Models & Mechanisms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1242/dmm.050914\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/23 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.050914","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/23 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.
Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.