UF Genetics Institute

Gainesville, FL, United States

UF Genetics Institute

Gainesville, FL, United States
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Wu K.,University of Florida | Wu K.,UF Genetics Institute | Li S.,University of Florida | Li S.,UF Genetics Institute | And 12 more authors.
Neurobiology of Learning and Memory | Year: 2012

We previously identified a set of 50 genes that were differentially transcribed in the hippocampal CA1 region of aged, learning-impaired rats compared to aged, superior learning animals during a Morris water maze paradigm. In the current study, we expressed three of these genes (Pctk1, Tcf12 and Ccnd1), which had shown increased transcription in aged, learning impaired rats, in the hippocampus of young rats using viral gene transfer and tested for learning and memory deficits at age 7-14. months. Pctk1 injected animals displayed a modest deficit in acquiring latency in both the Morris water maze and the reverse Morris maze. In the radial arm water maze paradigm, Pctk1, Tcf12 and Ccnd1 expressing animals all showed significant deficits in spatial working memory compared to controls. Rats injected with Ccnd1 and Tcf12, but not Pctk1, also showed a significant deficit in spatial reference memory in the radial arm water maze. Electrophysiological experiments revealed no difference in LTP in Ccnd1 and Pctk1 animals. However, LTD induced by low frequency stimulation was observed in control and Ccnd1 animals, but not in Pctk1 treated animals. In addition, neither Ccnd1 nor Pctk1 expression produced any detectable neuropathology. In contrast Tcf12 expressing animals displayed significant neurodegeneration in both CA1 and dentate gyrus. Several Tcf12 animals also developed tumors that appeared to be glioblastomas, suggesting that aberrant Tcf12 expression in the hippocampus is tumorigenic. Thus, behavioral experiments suggested that overexpression of Pctk1 and Ccnd1 produce a deficit in learning and memory, but electrophysiological experiments do not point to a simple mechanism. In contrast, the learning and memory deficits in Tcf12 animals are likely due to neuropathology associated with Tcf12 gene expression. © 2011 Elsevier Inc.


News Article | November 9, 2016
Site: www.sciencedaily.com

University of Florida researchers have identified cells targeted by a male hormone and found that an excess of that hormone at a specific time can cause genital defects in female mice. The findings appear in the Proceedings of the National Academy of Sciences. The study identifies a window of fetal development and a type of cell targeted by masculinizing hormones that cause a certain type of vaginal defect. "How the vagina and urethra separate is an interesting developmental question," said Christine Larkins, Ph.D., a research assistant professor in the department of molecular genetics and microbiology at the UF College of Medicine, part of UF Health. "Having two openings is something that is almost exclusively found in rodents and primates, including humans." Scientists have long known that prenatal exposure to androgens, such as the hormone testosterone, causes genital defects in females. Androgens act as masculinizing hormones, directing formation of male genitalia and preventing formation of a vaginal opening in boys. When a female embryo produces excessive amounts of androgen, it disrupts the development of the urethral and vaginal openings. Instead of developing as separate tubes with individual openings, they are born with only one opening. "Genital malformations cause very serious clinical issues," said Romano DeMarco, a UF Health physician in the department of urology. He listed problems such as incontinence, infertility and inability to have intercourse, as well as the psychosocial struggles of a physical deformity. Until now, many scientists assumed it was the quantity of androgen that dictates where the urethra and vagina attach in these malformations -- in milder defects the tubes join close to the natural opening, but in more severe defects, they can fuse near the bladder. Using mouse models, Larkins, working with Ana Enriquez, an undergraduate, and Martin Cohn, Ph.D., a professor in the department of molecular genetics and microbiology and a member of the UF Genetics Institute, demonstrated that the timing and duration of androgen exposure influence the severity of vaginal malformations. The researchers also identified a group of cells that guides the developing vagina to the correct position in the embryo. They report that androgen blocks the activity of those cells, causing the vagina to remain connected to the urethra. "This study really opens the door for us to get at the targets of androgen that are regulating this process," Larkins said. "Now that we know when and where androgen is acting, we can really define what's downstream of that to regulate this process." Genital malformations are among the most common birth defects in humans, affecting 1 in every 250 live births. "We know very little about external genital development, despite the high incidence of malformations," Cohn said. "The little bit that we do know is almost all from studies of males. There's a lot of catching up to do."


News Article | November 8, 2016
Site: www.eurekalert.org

University of Florida researchers have identified cells targeted by a male hormone and found that an excess of that hormone at a specific time can cause genital defects in female mice. The findings appear today (Nov. 7) in the Proceedings of the National Academy of Sciences. The study identifies a window of fetal development and a type of cell targeted by masculinizing hormones that cause a certain type of vaginal defect. "How the vagina and urethra separate is an interesting developmental question," said Christine Larkins, Ph.D., a research assistant professor in the department of molecular genetics and microbiology at the UF College of Medicine, part of UF Health. "Having two openings is something that is almost exclusively found in rodents and primates, including humans." Scientists have long known that prenatal exposure to androgens, such as the hormone testosterone, causes genital defects in females. Androgens act as masculinizing hormones, directing formation of male genitalia and preventing formation of a vaginal opening in boys. When a female embryo produces excessive amounts of androgen, it disrupts the development of the urethral and vaginal openings. Instead of developing as separate tubes with individual openings, they are born with only one opening. "Genital malformations cause very serious clinical issues," said Romano DeMarco, a UF Health physician in the department of urology. He listed problems such as incontinence, infertility and inability to have intercourse, as well as the psychosocial struggles of a physical deformity. Until now, many scientists assumed it was the quantity of androgen that dictates where the urethra and vagina attach in these malformations -- in milder defects the tubes join close to the natural opening, but in more severe defects, they can fuse near the bladder. Using mouse models, Larkins, working with Ana Enriquez, an undergraduate, and Martin Cohn, Ph.D., a professor in the department of molecular genetics and microbiology and a member of the UF Genetics Institute, demonstrated that the timing and duration of androgen exposure influence the severity of vaginal malformations. The researchers also identified a group of cells that guides the developing vagina to the correct position in the embryo. They report that androgen blocks the activity of those cells, causing the vagina to remain connected to the urethra. "This study really opens the door for us to get at the targets of androgen that are regulating this process," Larkins said. "Now that we know when and where androgen is acting, we can really define what's downstream of that to regulate this process." Genital malformations are among the most common birth defects in humans, affecting 1 in every 250 live births. "We know very little about external genital development, despite the high incidence of malformations," Cohn said. "The little bit that we do know is almost all from studies of males. There's a lot of catching up to do." This work was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases Grant K01 DK105077 (to C.E.L.) and NIH/National Institute of Environmental Health Sciences Grant R01 ES017099 (to M.J.C.).


Gorbatyuk M.S.,UF Genetics Institute | Gorbatyuk M.S.,University of North Texas Health Science Center | Shabashvili A.,UF Genetics Institute | Chen W.,UF Genetics Institute | And 13 more authors.
Molecular Therapy | Year: 2012

Accumulation of human wild-type (wt) α-synuclein (α-syn) induces neurodegeneration in humans and in experimental rodent models of Parkinson disease (PD). It also leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). We overexpressed glucose regulated protein 78, also known as BiP (GRP78/BiP), to test the hypothesis that this ER chaperone modulates the UPR, blocks apoptosis, and promotes the survival of nigral dopamine (DA) neurons in a rat model of PD induced by elevated level of human α-syn. We determined that α-syn activates ER stress mediators associated with pancreatic ER kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6) signaling pathways as well as proaoptotic CCAAT/-enhancer-binding protein homologous protein (CHOP) in nigral DA neurons. At the same time, overexpression of GRP78/BiP diminished α-syn neurotoxicity by down regulating ER stress mediators and the level of apoptosis, promoted survival of nigral tyrosine hydroxylase (TH) positive cells and resulted in higher levels of striatal DA, while eliminating amphetamine induced behavioral asymmetry. We also detected a complex between GRP78/BiP and α-syn that may contribute to prevention of the neurotoxicity caused by α-syn. Our data suggest that the molecular chaperone GRP78/BiP plays a neuroprotective role in α-syn-induced Parkinson-like neurodegeneration. © The American Society of Gene & Cell Therapy.


Matsuba C.,University of Florida | Lewis S.,University of Florida | Ostrow D.G.,University of Florida | Salomon M.P.,University of Florida | And 6 more authors.
G3: Genes, Genomes, Genetics | Year: 2012

Evidence is accumulating that individuals in poor physiologic condition may accumulate mutational damage faster than individuals in good condition. If poor condition results from pre-existing deleterious mutations, the result is "fitness-dependent mutation rate," which has interesting theoretical implications. Here we report a study in which 10 mutation accumulation (MA) lines of the nematode Caenorhabditis elegans that had previously accumulated mutations for 250 generations under relaxed selection were expanded into sets of "second-order" MA lines and allowed to accumulate mutations for an additional 150 generations. The 10 lines were chosen on the basis of the relative change in fitness over the first 250 generations of MA, five high-fitness lines and five low-fitness lines. On average, the mutational properties (per-generation change in mean relative fitness, mutational variance, and Bateman-Mukai estimates of genomic mutation rate and average mutational effect) of the high-fitness and low-fitness did not differ significantly, and averaged over all lines, the point estimates were extremely close to those of the firstorder MA experiment after 200 generations of MA. However, several nonsignificant trends indicate that low-fitness lines may in fact be more likely to suffer mutational damage than high-fitness lines. © 2012 Matsuba et al.


Sefah K.,University of Florida | Sefah K.,UF Genetics Institute | Bae K.-M.,University of Florida | Phillips J.A.,University of Florida | And 9 more authors.
International Journal of Cancer | Year: 2013

Cancer stem cells (CSC) represent a malignant subpopulation of cells in hierarchically organized tumors. They constitute a subpopulation of malignant cells within a tumor mass and possess the ability to self-renew giving rise to heterogeneous tumor cell populations with a complex set of differentiated tumor cells. CSC may be the cause of metastasis and therapeutic refractory disease. Because few markers exist to identify and isolate pure CSC, we used cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX) to create DNA aptamers that can identify novel molecular targets on the surfaces of live CSC. Out of 22 putative DNA sequences, 3 bound to ∼90% and 5 bound to ∼15% of DU145 prostate cancer cells. The 15% of cells that were positive for the second panel of aptamers expressed high levels of E-cadherin and CD44, had high aldehyde dehydrogenase 1 activity, grew as spheroids under nonadherent culture conditions, and initiated tumors in immune-compromised mice. The discovery of the molecular targets of these aptamers could reveal novel CSC biomarkers. Copyright © 2012 UICC.


Zhu B.,Beijing Institute of Technology | Jia H.,CAS Institute of Chemistry | Zhang X.,Beijing Institute of Technology | Chen Y.,UF Genetics Institute | And 5 more authors.
Analytical and Bioanalytical Chemistry | Year: 2010

A new, visible-light-excited and red-emitting fluorescent Ca2+ probe, STDBT, was synthesized, which consists of 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid as a Ca2+-chelating moiety and two benzothiazolium hemicyanine dyes as fluorophores. The spectral profiles of its free and Ca2+-bound forms were studied. Upon addition of Ca 2+, the fluorescence spectra of STDBT displayed a significant enhancement (about 48-fold) in fluorescence intensity and a 20-nm blueshift (from 600 to 580 nm) in the emission spectrum. Both the absorption and the excitation spectra of STDBT showed a very large (more than 100 nm) hypsochromic shift in the long-wavelength maxima upon binding with Ca2+. Interestingly, in contrast with the commonly used Ca2+ indicator Fluo-3, when the acetoxymethyl ester of STDBT enters into cells, it distributes both in the cytosol and the nucleus, but displays a very clear boundary between the two compartments. This allows STDBT to be used as a double targetable Ca2+ probe that can be used to report cytoplasmic Ca2+ and nuclear Ca2+ simultaneously. © Springer-Verlag 2010.


Norrie J.L.,University of Texas at Austin | Lewandowski J.P.,University of Texas at Austin | Bouldin C.M.,UF Genetics Institute | Bouldin C.M.,University of Washington | And 6 more authors.
Developmental Biology | Year: 2014

Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis. © 2014 Elsevier Inc.

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