Colleen and Garrett to present at Student Seminar Thursday (19.Nov) at noon in 2166 MERF

Colleen and Garrett will be presenting Student Seminar this week in 2166 MERF at noon. I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Garrett’s talk

Since its initial discovery in 1949, lithium continues to be prescribed to patients suffering from bipolar affected disorder (BPD).  However, the underlying mechanisms of how this drug elicits its mood-stabilizing effect remain unknown.  To help identify these lithium-responsive processes, we have used the dominant, X-linked Drosophila mutant Shudderer (Shu). This mutant is characterized by strong jerking and twitching as well as uncoordinated locomotion.  Interestingly, the severity of Shu phenotypes can be significantly reduced upon lithium administration(1). Our behavioral, anatomical and genetic investigations of this mutant have led to the following findings.  Lithium improves Shu mutant climbing and reduces the severity of the jerking phenotypes.  In contrast the same doses of lithium have no significant impact on the same behaviors in wild-type flies.  Shu mutants exhibit down-turned wings and an indentation of the dorsal thorax, a phenotype previously observed in mutants with neuronal excitability. Classic meiotic mapping suggests that the Shu mutation lies near chromosomal region 14D-15F.  Microarray gene expression profiling of the Shu mutant revealed that CanA-14F, which encodes a catalytic subunit of the Ca²⁺/calmodulin-dependent Ser/Thr protein phosphatase calcineurin is up-regulated 2.2-fold compared to wild-type.  To determine if a reduction in CanA-14F levels could improve the mutant phenotypes, hypomorphic mutant alleles of CanA-14F were introduced into the Shu background.  The resultant flies transheterozygous for Shu and the CanA-14F hypomorphic alleles showed a reduction in morphological defects as well as a significant improvement in behavior.  Lastly, expression of the endogenous inhibitor of calcineurin activity, nebula (nla) was sufficient to suppress the morphological phenotypes in Shu when driven in neurons.  Rescue was not observed when expressed in glia, muscle or fat bodies.  These data suggest that overexpression of CanA-14F, and a subsequent increase in calcineurin activity in the nervous system play a role in the manifestation of the Shu phenotypes.

Recent evidence in two human association studies has shown the calcineurin A subunit gene PPP3CC to be a risk factor in both schizophrenia and BPD (2, 3).  Furthermore, several calcineurin mutant mouse models show behavioral deficits reminiscent of those observed in schizophrenia and other mental disorders (4, 5).

1.            R. L. Williamson, Psychopharmacology (Berl) 76, 265 (1982).

2.            F. Mathieu et al., Behav Brain Funct 4, 2 (2008).

3.            D. J. Gerber et al., Proc Natl Acad Sci U S A 100, 8993 (Jul 22, 2003).

4.            T. Miyakawa et al., Proc Natl Acad Sci U S A 100, 8987 (Jul 22, 2003).

5.            C. J. Herzog, S. Miot, I. M. Mansuy, B. Giros, E. T. Tzavara, Eur J Pharmacol 580, 153 (Feb 2, 2008).

Erik Westin to present a Seminar

Our very own Erik Westin will be presenting a Seminar in conjunction with Free Radical and Radiation Biology.

Title:  The Modulation of ROS by Short Telomere Signaling”

When:  Thursday October 22, 2009

Time:  11:30 am

Place:  1117 MERF

Come out and show your support for Erik and learn about telomere signaling!

Special Symposium

A special Symposium will be held on Saturday, September 26, 2009 from 9am-5pm in Kollros Auditorium (101 Biology Building East).  Below is the list adn times for each of the speakers, as well as a link to each of their web pages.  Hope to see you there!

Program Schedule

9:00-9:10 Dr. Susan Gottesman (NIH): “Beyond the Central Dogma:  Regulation by Small RNAs and Protein Turnover”

9:55-10:40 Dr. Peter Moore (Yale):  “The Structural Basis of the Species-Specificity of Anti-Ribosomal Antibiotics”

10:40-11:05 Break

11:05-11:50 Dr. Sankar Adhya (NIH):  “The Puzzle of Lamda Prophage Stability”

11:50-12:35 Dr. David Soll (U of Iowa):  “A Unique View of the Evolution of a New Signal Transduction Pathway in Candida  Albicans“

12:35-2:05 Lunch break (on own)

2:05-2:50 Dr. Louis Reichardt (U of California, San Francisco):  “Straying off the Lambda Trail:  New Findings in the Wilderness of Brain Development”

2:50-3:35  Dr. Jeff Murray (U of Iowa):  “Genome Wide Association Studies, Disclose New Biology”

3:35-4:00 Break

4:00-4:45 Dr. Mario Capecchi (U of Utah):  “Modeling Human Cancers in the Mouse”

Erin and Di to present at Student Seminar Thursday (17.Sept) at noon in 2166 MERF

Erin and Di will be presenting Student Seminar this week in 2166 MERF at noon. I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Erin’s talk

Integrating vector systems are under current investigation as gene transfer vehicles in treatments for diseases such as cystic fibrosis (OMIM).   Integrating vectors such as retrovirus, lentivirus, and DNA transposons are beneficial in achieving long-term expression of therapeutic genes.  However, vector integration carries the potential for insertional mutagenesis, resulting in aberrant expression of host genes.  Thus, it would be beneficial to develop vectors that target integration to a specific genomic region.  This work aims to direct the DNA transposon vector piggyBAC to a specific locus in the genome.  This strategy attempts to achieve site-directed integration through interaction of the DNA binding domain-modified transposase gene with its target in a human cell line.  We have modified a codon-optimized piggyBAC transposase with the bacterial LacI DNA binding domain in an N-terminal fusion construct.  Transposition assays showed that the modified transposase is active in human cells.  Excision assays indicated that the modified transposase excises precisely.  Moreover, we recovered intact transposase-genomic junctions from cells in which the modified transposase was delivered to catalyze transgene integration.  These data indicate that in addition to precise excision from the transposon plasmid, the modified transposase can carry out correct integration reactions.  Taken together, these results support the hypothesis that a piggyBAC transposase modified with a DNA binding domain can direct integration to a specific site in the genome.  We are currently testing this in a proof-of-principle experiment in which we used a LacI-modified transposase to direct integration in a human cell line containing the target LacO DNA binding sites stably integrated at a single locus.  Site-directed integration is an important step in developing safe and effective integrating vectors for therapeutic gene transfer applications.

Background for Di’s talk

Hypertension is defined as systolic blood pressure (SBP) over 140 mmHg and/or diastolic blood pressure (DBP) over 90 mmHg. It is an established risk factor for a range of diseases including obesity, diabetes, stroke and renal defects. Renin-Angiotensin System (RAS) plays an essential role in blood pressure regulation. Within this system, Renin (OMIM) is the rate-limiting enzyme in generating downstream effector angiotensin peptides. Renin is conventionally recognized as a secreted enzyme from renal JG cells. However, accumulating evidence support the existence and function of a novel Renin isoform that is retained intracellularly. We hypothesis that intracellular renin (icRen) plays a discrete role from its secreted counterpart (sRen), especially in the brain, to fine tune heart rate and blood pressure control via the central nervous system. I have completed a sRen-specific knockout mouse model during my PhD training. They exhibited lower blood pressure and renal atrophy due to the lack of sRen that is abundant in the kidney. This implicates that sRen is a vital isoform in the kidney and preservation of icRen mainly in the brain is not sufficient to rescue lethality.

Special Symposium Announcement

Sara and Danielle to present at Student Seminar Thursday (20.August) at noon

Sara and Danielle will be presenting Student Seminar this week in 106 BBE at noon. I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Sara’s talk

The existence of ancient asexual lineages in nature contradicts the current prevailing hypotheses regarding the apparent advantages of sexual over asexual reproduction.  Bdelloid rotifers are one such putative ancient asexual group.  Interestingly, meiosis-specific genes have been identified in the genomes of multiple bdelloid species, as well as in their facultatively sexual sister taxa, monogonont rotifers.  This proposed work will explore functional implications of the presence of these genes through the following specific aims: 1. Complete meiotic gene inventory of monogonont rotifers.  2. Analyze expression patterns of meiotic genes in monogonont and bdelloid cultures.  3. Examine location and timing of meiotic gene expression in monogononts and bdelloids.  This work will examine the potential for meiosis in bdelloids as well as the possibility of neo-functionalization of genes not known to be involved in cellular processes outside of meiosis.

Background for Danielle’s talk

Chiasmata play a major role in meiosis by helping to properly join homologous chromosome pairs, which is necessary for recombination and proper segregation. Male Drosophila, however, are unique amongst nearly all other male eukaryotes: they undergo achiasmatic meiosis. During spermatogenesis, the germ cell proceeds through meiosis and divides into four haploid gametes without formation of chiasmata or recombination. A number of genes have been found which play a role in achiasmatic meiosis in Drosophila, two of which arose from gene duplication events (Stromalin in Meiosis (snm) and Australin(aust)). These genes are both male- and meiosis-specific, in contrast to their paralogs (Stromal Antigen (SA) and Borrealin-related (borr)) which are ubiquitously expressed and have important roles in both mitosis and meiosis. To better understand how achiasmatic meiosis evolved in flies, I will trace the origin of the snm and aust gene duplications through degenerate PCR, sequencing and phylogenetic analysis in fly species throughout the Dipteran clade. This will pinpoint when during Dipteran evolution the duplication event(s) which gave rise to these genes occurred, and potentially indicate the origin of achiasmatic meiosis. Currently, partial gene sequences have been amplified from 19 Dipteran species outside of the Drosophila clade. Phylogenetic analysis of these sequences shows that they are orthologs of SA and not snm. This suggests that either snm is Drosophila-specific or that it may be evolving rapidly and thus difficult to amplify by degenerate PCR. Degenerate primers are also being used to amplify borr and aust in Dipterans. Future work will involve using deep sequencing to examine the expression levels of genes involved in chiasmatic meiosis in flies within the Schizophora group. If genes that are involved in chiasmata formation are not expressed, meiosis in that species might be achiasmatic, even if snm, aust, and other genes involved in Drosophila achiasmatic meiosis are not present. The expression of achiasmatic meiosis genes will also be examined to determine whether they are testes-specific in all species with these genes.

Yan to present at Student Seminar Thursday (6.August) at noon

Yan will be presenting Student Seminar this week in CBRB 2289 at noon. I have asked him to provide a brief overview for his talk. Hope to see you there!

Background for Yan’s talk

Bardet-Biedl Syndrome (BBS) is a phenotypically variable autosomal recessive disorder involving genes that map to twelve known loci. The disoder is characterized by a combination of clinical findings that include obesity, photoreceptor degeneration, polydactyl and hypogenitalism. Our lab has created several BBS knock-out (KO) mice lines such as Bbs7 -/-. All the KO mice are obese after five-month age. Furthermore, they show resistance to leptin compared to normal micec. We hypothesize that BBS heterozygous mice show obesity because of a dosage effect. To test this hypothesis, we examined body weight, fat percent and leptin level of Bbs7 heterozygous mice, and whether they are resistant to leptin. The leptin level of Bbs7 heterozygous male mice are higher than those of WT when they are 30-week old. 24-week old BBS7 +/- male mice are sensitive to leptin. These data suggest that leptin resistance in Bbs7 +/- male mice is age-dependent.

Leah and John to present at Student Seminar Thursday (23.July) at noon

Leah and John will be presenting Student Seminar this week in CBRB 2289 at noon.  I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Leah’s talk

The role of Irf6 in tissue regeneration

Tissue regeneration is critical to life in order to restore the protective barrier to the environment and to maintain homeostasis.  The skin is composed of two tissues: the dermis and the epidermis.  The epidermal cells, keratinocytes, migrate and proliferate in order to cover injured tissue.  IRF6 is expressed in the epidermis, which is where this work is focused.  Mutations in IRF6 OMIM) cause two autosomal dominant orofacial clefting syndromes: van der Woude (VWS) and popliteal pterygium (PPS).  In addition to these two syndromes, variants in IRF6 contribute 18% risk to non-syndromic forms of cleft.  Mice homozygous mutant for Irf6 exhibit skin anomalies in addition to cleft palate, which include oral adhesions and a hyperproliferative epidermis. The epidermis is also lacking the outer two layers, thus these mice lack barrier function and are perinatal lethal.  Proliferation is abnormal in mice lacking Irf6, and this is a crucial cellular process during tissue regeneration.  Thus, we hypothesize that IRF6 plays a role in tissue regeneration.

Background for John’s talk

I would introduce and report the current progress of my current project, “Quantitative trait locii Association Study of Blood Pressure Variability,” a collaborative study between our lab and Dr Miao Chaoyu of Shanghai. This project involves genomewide microsatellite genotyping of Spontaneously Hypertensive Rats (SHR), a rat model of hypertension, and the line that SHR is derived from, the Wistar-Kyoto (WKY), and subsequent computational analysis. This project is still underway.

Historical Science Tweets via Twitter

Hilarious post over @ PHD comics.  Who knew Watson’s ire for Pauling:)

Abe and Tara to present at Student Seminar Thursday (9.July) at noon

Abe and Tara will be presenting Student Seminar this week

in CBRB 2289 at noon.  I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Abe’s talk

Hearing impairment is the most common congenital deficit worldwide, affecting at least one of every five hundred neonates. In the Smith Lab, I am working toward gene therapy for hearing loss. Gene therapy targeting the inner ear offers promise for treatment of genetic forms of hearing loss.

There are a variety of cell types within the inner ear. Non-sensory supporting cells of the cochlea serve as the primary targets of intervention to induce hair cell regeneration. Cochlear supporting cells also express GJB2 and GJB6, mutations in which are the most common cause of autosomal recessive non-syndromic hearing loss (DFNB1) in many populations. The promise of hair cell regeneration and the potential for treatment of connexin-related deafness disorders are compelling reasons to identify vectors with tropism for supporting cells of the inner ear.

To target the inner ear we are using embryonic murine otocyst injections, a technique developed and optimized for in utero gene transfer by Bedrosian and colleagues (Mol Ther. 2006 Sep;14(3):328-35). They showed that an adeno-associated viral vector (AAV2/1) will safely and efficiently transduce sensory hair cell progenitors in the embryonic murine otocyst, the precursor to inner ear structures. However, AAV2/1 transduction of supporting cells in the inner ear was significantly less efficient. Given the variety of cell types in the inner ear and the genetic heterogeneity of hearing loss, viral tropism is an important consideration when selecting a vector for gene transfer. In student seminar this week I will report on progress to identify an appropriate vector for safe and efficient in utero gene transfer to the supporting cells of the developing mouse inner ear.

Background for Tara’s talk

Title: Contributions of genes in the complement system to the pathogenesis of atypical hemolytic uremic syndrome
Abstract: Atypical hemolytic uremic syndrome (aHUS, OMIM) is characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. aHUS is far less common and more severe than typical HUS, which is caused by E. coli infection and manifests as diarrheal illness. Anecdotally aHUS is a rare disease with an estimate of a total of 600 cases reported in the USA. The pathogenesis of the disease is linked to dysregulation of the alternative pathway of the complement cascade Mutations in the complement regulators factor H (CFH), membrane cofactor protein (MCP), and factor I (CFI) as well as complement proteins C3 and factor B (CFB), and have been implicated in aHUS. Since only 50 percent of aHUS patients have mutations in known disease causing genes, we hypothesize that there are other genes associated with aHUS.  We have chosen to prioritize genes in the alternative pathway as well as the terminal pathway of the complement cascade. The focus of my talk will be to provide an update of the candidate genes that we have sequenced in these patients paying particular attention to those in which we have found interesting variants.