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Item Embryonic and not maternal trisomy causes developmental attenuation in the Ts65Dn mouse model for Down syndrome(Wiley-Liss, Inc., 2010) Blazek, Joshua D.; Billingsley, Cherie N.; Newbauer, Abby; Roper, Randall J.Trisomy 21 results in Down syndrome (DS) and causes phenotypes that may result from alterations of developmental processes. The Ts65Dn mouse is the most widely used genetic and phenotypic model for DS. We used over 1,500 offspring from Ts65Dn and two nontrisomic genetically similar control strains to investigate the influence of trisomy on developmental alterations and number of offspring. For the first time, we demonstrate gross developmental attenuation of Ts65Dn trisomic offspring at embryonic day (E) 9.5 and E13.5 and show that the major determinant of the developmental changes is segmental trisomy of the embryo and not the trisomic maternal uterine environment. Maternal alleles of nontrisomic genes linked to Pde6b may also influence the development of Ts65Dn offspring. Both developmental attenuation and the contribution of trisomic and nontrisomic genes are important components in the genesis of DS phenotypes.Item A neural crest deficit in down syndrome mice is associated with deficient mitotic response to Sonic hedgehog(Elsevier, 2009) Roper, Randall J.; VanHorn, Justin F.; Cain, Colyn C.; Reeves, Roger H.Trisomy 21 results in phenotypes collectively referred to as Down syndrome (DS) including characteristic facial dysmorphology. Ts65Dn mice are trisomic for orthologs of about half of the genes found on human chromosome 21 and exhibit DS-like craniofacial abnormalities, including a small dysmorphic mandible. Quantitative analysis of neural crest (NC) progenitors of the mandible revealed a paucity of NC and a smaller first pharyngeal arch (PA1) in Ts65Dn as compared to euploid embryos. Similar effects in PA2 suggest that trisomy causes a neurocristopathy in Ts65Dn mice (and by extension, DS). Further analyses demonstrated deficits in delamination, migration, and mitosis of trisomic NC. Addition of Sonic hedgehog (Shh) growth factor to trisomic cells from PA1 increased cell number to the same level as untreated control cells. Combined with previous demonstrations of a deficit in mitogenic response to Shh by trisomic cerebellar granule cell precursors, these results implicate common cellular and molecular bases of multiple DS phenotypes.Item Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes(Wiley-Liss, Inc., 2004-05-14) Olsen, L.E.; Roper, Randall J.; Baxter, Laura L.; Carlson, E.J.; Epstein, C.J.; Reeves, R.H.Two mouse models are widely used for Down syndrome (DS) research. The Ts65Dn mouse carries a small chromosome derived primarily from mouse chromosome 16, causing dosage imbalance for approximately half of human chromosome 21 orthologs. These mice have cerebellar pathology with direct parallels to DS. The Ts1Cje mouse, containing a translocated chromosome 16, is at dosage imbalance for 67% of the genes triplicated in Ts65Dn. We quantified cerebellar volume and granule cell and Purkinje cell density in Ts1Cje. Cerebellar volume was significantly affected to the same degree in Ts1Cje and Ts65Dn, despite that Ts1Cje has fewer triplicated genes. However, dosage imbalance in Ts1Cje had little effect on granule cell and Purkinje cell density. Several mice with dosage imbalance for the segment of the Ts65Dn chromosome not triplicated in Ts1Cje had phenotypes that contrasted with those in Ts1Cje. These observations do not readily differentiate between two prevalent hypotheses for gene action in DS.Item Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice(2006-01-23) Roper, Randall J.; Baxter, Laura L.; Saran, Nidhi G.; Klinedinst, Donna K.; Beachy, Philip A.; Reeves, Roger H.Trisomy 21 is the cause of Down's syndrome (DS) which is characterized by a number of phenotypes, including a brain which is small and hypocellular compared to that of euploid individuals. The cerebellum is disproportionately reduced. Ts65Dn mice are trisomic for orthologs of about half of the genes on human chromosome 21 and provide a genetic model for DS. These mice display a number of developmental anomalies analogous to those in DS, including a small cerebellum with a significantly decreased number of both granule and Purkinje cell neurons. Here we trace the origin of the granule cell deficit to precursors in early postnatal development, which show a substantially reduced mitogenic response to Hedgehog protein signaling. Purified cultures of trisomic granule cell precursors show a reduced but dose-dependent response to the Sonic hedgehog protein signal in vitro, demonstrating that this is a cell-autonomous deficit. Systemic treatment of newborn trisomic mice with a small molecule agonist of Hedgehog pathway activity increases mitosis and restores granule cell precursor populations in vivo. These results demonstrate a basis for and a potential therapeutic approach to a fundamental aspect of CNS pathology in DS.Item Genetic analysis of triplicated genes affecting sex-specific skeletal deficits in Down syndrome model mice(bioRxiv, 2025-02-01) Sloan, Kourtney; Piner, Kristina M.; Arachchige, Pathum Randunu Nawarathna Kandedura; Goodlett, Charles R.; Herault, Yann; Olbricht, Gayla R.; Wallace, Joseph M.; Roper, Randall J.; Biology, School of ScienceDown syndrome (DS) is caused by triplication of human chromosome 21 (Hsa21), resulting in skeletal insufficiency and altered postnatal bone development in individuals with DS. DS mouse models have shown similar deficits to humans with DS, mimicking differences between ages, sexes, and bone compartments. The historic mouse model, Ts65Dn, has provided much of the mechanistic insight behind these DS-related skeletal deficits, but there are concerns over its genetic construct validity. Ts65Dn mice have an additional 60 trisomic genes that are homologous to Hsa6. These genes, acting either directly or through interactions with trisomic, Hsa21-homologous or disomic genes, may produce phenotypes not related to DS; so, Ts66Yah mice were derived to remove these genes. After assessing individual densitometric and morphometric parameters in femurs, skeletal phenotypes were directly compared between male and female Ts65Dn and Ts66Yah mice at postnatal day (P) 36 and 6-weeks and between male mice at 16-weeks using multivariate principal components analyses on these parameters. These comparisons confirmed male Ts66Yah mice have trabecular and cortical deficits similar to male Ts65Dn mice at all ages. In contrast, female Ts66Yah mice lacked trabecular deficits evident in female Ts65Dn mice at P36, but both ages had similar cortical deficits. Copy number normalization of Dyrk1a, a trisomic, Hsa21-orthologous gene, failed to rescue deficits in male or improve trabecular bone in female Ts66Yah mice at P36 as observed in Ts65Dn mice. Thus, mechanisms behind trabecular phenotypes in both sexes of Ts66Yah mice likely differ from those of Ts65Dn mice. Overall, the trisomic, Hsa6-homologous genes in Ts65Dn mice may result in differences in trabecular phenotypes or mechanisms prior to 6 weeks but do not impact later trabecular or cortical phenotypes.Item Disruption of bone development and homeostasis by trisomy in Ts65Dn Down syndrome mice(Elsevier, 2011) Blazek, Joshua D.; Gaddy, Anna; Meyer, Rachel; Roper, Randall J.; Li, Jiliang; Biology, School of ScienceDown syndrome (DS) is a genetic disorder resulting from trisomy 21 that causes cognitive impairment, low muscle tone and craniofacial alterations. Morphometric studies of the craniofacial and appendicular skeleton in individuals with DS suggest that bone development and homeostasis are affected by trisomy. The Ts65Dn mouse model has three copies of approximately half the genes found on human chromosome 21 and exhibits craniofacial skeletal and size differences similar to those observed in humans with DS. We hypothesized that Ts65Dn and euploid mice have distinct differences in bone development and homeostasis influencing both the craniofacial and appendicular skeletal phenotypes. Quantitative assessment of structural and mechanical properties of the femur in Ts65Dn and control mice at 6 and 16 weeks of age revealed significant deficiencies in trabecular and cortical bone architecture, bone mineral density, bone formation, and bone strength in trisomic bone. Furthermore, bone mineral density and dynamic dentin formation rate of the skull and incisor, respectively, were also reduced in Ts65Dn mice, demonstrating that trisomy significantly affects both the craniofacial and appendicular skeleton.Item Sensory Neuron Development and Skeletal Deficits in Down Syndrome(2025-07) Thomas, Jared R.; Roper, Randall J.; Wallace, Joseph M.; Li, Jiliang; Hardy, Tabitha M.; Allen, Matthew R.All individuals with Down syndrome (DS) present with low bone mineral density (BMD) and neurodevelopmental delays. Altered skeletal development and homeostasis result in skeletal abnormalities observed in humans with DS and DS mouse models increasing the risk of early onset osteoporosis. Exercise or physical activity increases BMD and decreases the risk of osteoporosis. Reduced sensory nerve function and decreased innervation leads to impaired skeletal development and decreased skeletal adaptation to mechanical loads. We studied the impact of triplicated Hsa-21 orthologues, particularly Dyrk1a, on sensory neuron development, function and skeletal innervation, and skeletal adaptation to mechanical loads in DS-related skeletal phenotypes. We hypothesized that i) triplication of Dyrk1a disrupts communication between bone and peripheral sensory neurons during development leading in impaired skeletal development and adaptation and ii) normalization of Dyrk1a will rescue skeletal deficits associated with DS by restoring morphological and functional deficits of sensory neurons. Neuropeptide calcitonin gene-related peptide (CGRP), found in sensory nerve fibers innervating bone and the periosteum, is released in response to mechanical stimulation and promotes bone formation. Ts65Dn male mice (at 6-weeks) released significantly more CGRP in response to capsaicin stimulation compared to controls. Both Ts65Dn and Dp1Tyb male mice (16-weeks) had decreased sensory neurons in L4 dorsal root ganglion (DRG). There were no differences in sensory or sympathetic innervation in Ts65Dn, while Dp1Tyb male mice had slightly increased sympathetic innervation of the distal femur. Mechanical stimulation was performed in male and female Dp1Tyb and control mice with expected and reduced Dyrk1a copy number in sensory neurons. Loading the left tibiae at 1500 με, but not 1800 με for 4 weeks improved trabecular and cortical architecture in male and female mice across all genotypes. These data suggest that triplicated Hsa-21 orthologues impair sensory neuron development and function, potentially disrupting communication between bone and the sensory nervous system during skeletal development and adaptation. Loading may improve bone architecture in DS mice, but the limited response highlights the need to find optimal strain levels to produce an anabolic response and identify Hsa-21 genes that affect skeletal development.Item Molecular Characterization of the Translocation Breakpoints in the Down Syndrome Mouse Model, Ts65Dn(Springer, 2011) Reinholdt, Laura G.; Ding, Yueming; Gilbert, Griffith J.; Czechanski, Anne; Solzak, Jeffrey P.; Roper, Randall J.; Johnson, Mark T.; Donahue, Leah Rae; Lutz, Cathleen; Davisson, Muriel T.; Biology, School of ScienceTs65Dn is a mouse model of Down syndrome: a syndrome that results from chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer's disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu17(16)), with breakpoints that have not been defined previously. To molecularly characterize the Chrs 16 and 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput paired-end sequencing approach. Analysis of paired-end reads flanking the Chr 16, Chr 17 junction on Mmu17(16) and de novo assembly of the reads directly spanning the junction provided the precise locations of the Chrs 16 and 17 breakpoints at 84,351,351 and 9,426,822 bp, respectively. These data provide the basis for low-cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.Item Compromised Femoral and Lumbovertebral Bone in the Dp(16)1Yey Down Syndrome Mouse Model(Elsevier, 2024) Lamantia, Joshua; Sloan, Kourtney; Wallace, Joseph M.; Roper, Randall J.; Biology, School of ScienceDown syndrome (DS), affecting ∼1 in 800 live births, is caused by the triplication of human chromosome 21 (Hsa21). Individuals with DS have skeletal features including craniofacial abnormalities and decreased bone mineral density (BMD). Lowered BMD can lead to increased fracture risk, with common fracture points at the femoral neck and lumbar spine. While the femur has been studied in DS mouse models, there is little research done on the vertebrae despite evidence that humans with DS have affected vertebrae. Additionally, it is important to establish when skeletal deficits occur to find times of potential intervention. The Dp(16)1Yey DS mouse model has all genes triplicated on mouse chromosome 16 orthologous to Hsa21 and displayed deficits in long bone, including trabecular and cortical deficits in male but not female mice, at 12 weeks. We hypothesized that the long bone and lumbovertebral microarchitecture would exhibit sexually dimorphic deficits in Dp(16)1Yey mice compared to control mice and long bone strength would be diminished in Dp(16)1Yey mice at 6 weeks. The trabecular region of the 4th lumbar (L4) vertebra and the trabecular and cortical regions of the femur were analyzed via micro-computed tomography and 3-point bending in 6-week-old male and female Dp(16)1Yey and control mice. Trabecular and cortical deficits were observed in femurs from male Dp(16)1Yey mice, and cortical deficits were seen in femurs of male and female Dp(16)1Yey mice. Male Dp(16)1Yey femurs had more deficits in bone strength at whole bone and tissue-estimate level properties, but female Dp(16)1Yey mice were also affected. Additionally, the L4 of male and female Dp(16)1Yey mice show trabecular deficits, which have not been previously reported in a DS mouse model. Our results indicate that skeletal deficits associated with DS occur early in skeletal development, are dependent on skeletal compartment and site, are sex dependent, and potential interventions should likely begin early in skeletal development of DS mouse models.Item Commonality in Down and Fetal Alcohol Syndromes(Wiley, 2013) Solzak, Jeffrey P.; Liang, Yun; Zhou, Feng C.; Roper, Randall J.; Biology, School of ScienceBackground: Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from craniofacial abnormalities to cognitive impairment. Despite different origins, we report that in addition to sharing many phenotypes, DS and FAS may have common underlying mechanisms of development. Methods: Literature was surveyed for DS and FAS as well as mouse models. Gene expression and apoptosis were compared in embryonic mouse models of DS and FAS by qPCR, immunohistochemical and immunoflurorescence analyses. The craniometry was examined using MicroCT at postnatal day 21. Results: A literature survey revealed over 20 comparable craniofacial and structural deficits in both humans with DS and FAS and corresponding mouse models. Similar phenotypes were experimentally found in pre- and postnatal craniofacial and neurological tissues of DS and FAS mice. Dysregulation of two genes, Dyrk1a and Rcan1, key to craniofacial and neurological precursors of DS, was shared in craniofacial precursors of DS and FAS embryos. Increased cleaved caspase 3 expression was also discovered in comparable regions of the craniofacial and brain precursors of DS and FAS embryos. Further mechanistic studies suggested overexpression of trisomic Ttc3 in DS embyros may influence nuclear pAkt localization and cell survival. Conclusions: This first and initial study indicates that DS and FAS share common dysmorphologies in humans and animal models. This work also suggests common mechanisms at cellular and molecular levels that are disrupted by trisomy or alcohol consumption during pregnancy and lead to craniofacial and neurological phenotypes associated with DS or FAS.