“The Development and Evolution of Vertebrate Morphology”

C. Peter Verrijzer, PhD

Abstract:

The incidence of obesity is increasing at an alarming rate and this worldwide epidemic represents an ominous predictor of increases in diseases such as type 2 diabetes and metabolic syndrome. Epidemiological and animals studies suggest that alteration of the metabolic and hormonal environment during critical periods of development is associated with increased risks for obesity, hypertension, and type 2 diabetes in later life. There is general recognition that the developing brain is more susceptible to environmental insults than the adult brain. In particular, there is growing appreciation that developmental programming of neuroendocrine systems by the perinatal environment represents a possible cause for these diseases. This seminar will discuss potential periods of vulnerability for the development of hypothalamic neurons involved in feeding regulation. It will also provide an overview of recent evidence concerning the action of perinatal hormones (including leptin and ghrelin) in programming the development and organization of hypothalamic circuits. Finally, this presentation will highlight recent findings on the role of autophagy in the development of hypothalamic feeding pathways.

Sanker Ghosh, PhD

Abstract:



Some new germline mutations that arise in the testis may confer a selective advantage to the mutated germ cell relative to non-mutated cells. Theoretically, if a new mutation provided a germline selective advantage it could increase the frequency at which the mutated allele was introduced into the population by orders of magnitude even though, much to the species detriment, it reduced the fitness of the individuals that inherited it. We have shown examples of positive germline selection for three human disease mutations that arise sporadically each generation at frequencies ranging from 1/2,000 to 1/70,000 births. These sporadic disease cases occur at rates 100-1,000 times greater than would be expected based on what we know about genome average mutation rates. Using a testis dissection/mutation detection approach along with mathematical modeling we have shown that the high frequency of these de novo disease mutations cannot be explained by hyper-mutation at the disease-causing sites. Instead, our data are consistent with the idea that the newly mutated germline stem cells have a proliferative advantage over non-mutated stem cells resulting in germline mosaicism. Plausible molecular mechanisms can explain the selective advantage for each of the three disease mutations. Others previously suggested that alleles conferring a selective advantage in the germline may be disadvantageous in the adult and might lead to “mitotic drive” systems that increase the mutational load of a population. The three disease mutations we examined may be realizations of this idea.

Charles B. Kimmel, PhD
Professor Emeritus of Biology, Institute of Neuroscience, University of Oregon

Abstract:



Might development constrain or bias the course of evolution? A venerable hypothesis is that some morphologies are ‘impossible’ – forbidden because of the way that development works. However, we examined the shapes of the four opercular bones in diverse teleosts and found no evidence for forbidden morphologies or developmental constraint. We account for our observed rich shape variation by noting that evolutionary shape changes in discrete regions of bone are dissociable from changes in other regions. Dissociation is a hallmark of modularity, where modules are relatively autonomous developmental building blocks. Modularity should permit evolutionary flexibility, for example modularity can facilitate keeping of functional fits among neighboring bones that are evolving new shapes. We tested this hypothesis with stickleback and salmonids, and found that the locations in the skull where evolutionary changes in bone shape occur strikingly predict module boundaries. With zebrafish we find that bone shaping during development occurs in phases. Each phase, or developmental module, is marked by a distinctive pattern of osteoblast arrangement and bone outgrowth, and mutational analyses reveal that separate phases are under separate genetic control. Hence the zebrafish work provides insight about the cellular and developmental genetic basis of skull modularity.

Richard Simerly, PhD
Professor, Department of Pediatrics, Professor, Biological Sciences, Neurobiology, Deputy Director, Saban Research Institute, Director, Developmental Neuroscience Program, Childrens Hospital Los Angeles, Keck School of Medicine of the University of Southern California

Abstract:



The developing hypothalamus is exposed to two successive environments: One in utero and the other postnatal. As neural circuits form in the hypothalamus during these perinatal periods, environmental signals impact hypothalamic development in ways that impact homeostasis throughout the life of an individual. Circuits that control body weight develop under the influence of the adipocyte-derived hormone leptin during discrete temporal domains suggesting that there are region- specific, hormonally directed mechanisms governing the assembly of homeostatic circuits. Recent findings indicate the ability of leptin to specify patterns of neuronal connectivity in the hypothalamus may differentially impact distinct components of autonomic regulation. Moreover, leptin appears to exert these actions direct neurrophic influence on hypothalamic neurons that include promotic neurite extension, specifying patterns of axonal targeting, and influence cell type specific alterations in synaptic density. Thus, leptin is a major developmental factor that may mediate metabolic programming of hypothalamus by a variety of environmental factors including nutrition.





Biography:



Richard Simerly is Professor of Pediatrics at the Keck School of Medicine of the University of Southern California and Professor of Biological Sciences in the division of Neurobiology at USC. He also serves as Deputy Director of The Saban Research Institute and Director of the Developmental Neuroscience Program in the Saban Research Institute of CHLA. Before joining the CHLA faculty, Dr. Simerly was Senior Scientist at the Oregon National Primate Research Center, and a faculty member of the Neuroscience Graduate Program and Department of Cell and Developmental Biology of the Oregon Health & Science University in Portland, Oregon. Dr. Simerly is a graduate of The University of California, Berkeley and received his Ph.D. from the University of California, Los Angeles. He was also a postdoctoral fellow and Senior Research Associate at The Salk Institute for Biological Studies and Adjunct Assistant Professor in The Neurosciences Department of The University of California, San Diego. Dr. Simerly is an internationally recognized expert on hormonal control of brain development and his current research is focused on understanding how forebrain circuits that control body weight and energy metabolism develop in

response to endocrine and nutritional cues. Previous work from his laboratory demonstrated that the fat-derived hormone leptin represents a significant factor directing brain development. Dr. Simerly’s laboratory is currently studying how leptin signaling and neonatal nutrition impact development of hypothalamic neuronal circuits that control feeding and glucose metabolism.

Abstract:
Only studies of the past seven years have revealed a picture for when, how and why Hsp90 gets exported by both normal and tumor cells. Normal cells secrete Hsp90 in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90 for tissue invasion. A well-characterized function of secreted Hsp90a is to promote cell motility, a crucial event for both wound healing and cancer. The pro-motility activity of secreted Hsp90a resides within a 115-aa fragment, called F-5, between the linker region and middle domain. In normal tissue, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy. In cancer, drugs that selectively target the F-5 region of secreted Hsp90 by cancer cells is predicted to be more effective and less toxic than those that target the ATPase of the intracellular Hsp90. USC owns both patents of these applications.



Biography:
After receiving his college education in Biology Major from Xinjiang University, People’s Republic of China, Dr. Li came the US in 1985. He received a MS degree in 1988 and a PhD degree in 1991 from the Department of Developmental Biology and Cancer at the Albert Einstein College of Medicine, Bronx, New York City. Following a two-year post-doctoral/instructor fellowship with Dr. Joseph Schlessinger (Professor and Chairman) in the Department of Pharmacology at New York University Medical Center, he joined the faculty of the Ben May Institute for Cancer Research at the University of Chicago in the fall of 1993 as an Assistant Professor. He came to USC in the beginning of 1999. He is currently a Professor in the Department of Dermatology and the USC-Norris Cancer Center and the Director of the USC GMCB Graduate Program. His research programs have been supported from NIH since 1995.

Abstract:
Although animal polyomaviruses, such as SV40, have been critical models in cancer research for over one-half century, polyomaviruses have not--until recently--been linked to human cancer. Using digital transcriptome subtraction, Merkel cell polyomavirus (MCV) was discovered in 2008 to infect most Merkel cell carcinomas, the most severe form of skin cancer. Normally, MCV is an common and asymptomatic infection of the human skin. In Merkel cell tumors, however, the virus integrates and undergoes mutations that eliminate viral replication but allow continued expression of viral oncogenes. MCV and MCC reveal a new model for carcinogenesis in which a rare combination of xenomutations to healthy skin flora initiate a deadly cancer. Using new sequencing technologies, the causes previously-unsuspected viral cancers can be uncovered and clues for new rational drug therapies can be designed.


Biography:

Patrick S. Moore, MD, MPH is a Distinguished and American Cancer Society (ACS) Professor in the Department of Microbiology and Molecular Genetics, University of Pittsburgh. He is Director of the Cancer Virology Program for the University of Pittsburgh Cancer Institute. Dr. Moore is recognized for his role, together with Dr. Yuan Chang—also an ACS Professor, in discovering and characterizing Kaposi sarcoma herpesvirus (KSHV or HHV8) and Merkel cell polyomavirus (MCV), the two most recently recognized human tumor viruses. Dr. Moore and Chang’s laboratory maintain an active focus on basic and translational research for both KSHV and MCV. Dr. Moore has received the General Motors Cancer Research Foundation Mott Award, the Robert Koch Prize, the Meyenburg Cancer Research Prize as well as other awards, and 21 patents. He is a Thomson Reuter ISI Highly Cited Researcher with over 17,000 scientific citations since 1992. A native of Salt Lake City, he graduated from Westminster College in 1977. He received medical and graduate degrees from the University of Utah, Stanford University and University California, Berkeley and trained at the Centers for Disease Control as an Epidemic Intelligence Service (EIS) officer.

Kunliang Guan, PhD
Professor of Pharmacology, University of California San Diego

“The mTOR Pathways in Nutrient Sensing, Autophagy, Cell Growth, and Cancer”

Abstract:
The mammalian target of rapamycin (mTOR) is a central cell growth regulator and its hyperactivation is commonly observed in human cancers. mTOR forms two distinct structural and functional complexes, mTORC1 and mTORC2. mTORC1 promotes cell growth and cell size by stimulating protein synthesis and inhibiting autophagy. A wide range of signals, including nutrients, energy levels and growth factors, are known to control MTORC1 activity. The TSC1 /2 tumor suppressors and Rheb GTPase are key upstream regulators mediating signals from growth factors to mTORC1 activation. AMPK inhibits mTORC1 in response to energy stress while the Rag GTPases stimulate mTORC1 in response to amino acid sufficiency. mTORC1 suppresses autophagy by phosphorylating and inhibiting the autophagy initiating kinase ULK1/2. An intricate network of mTOR regulation and its role in cell growth and tumorigenesis have been revealed.

Biography:

Kun-Liang Guan, Professor of Pharmacology, University of California San Diego (2007-). B.S. (1982) Hangzhou University, China; Ph.D. (1989) Purdue University; Assistant professor to professor (1992-2007) and Halvor Christensen Professor (2003-2007), University of Michigan. MacArthur Fellow (1998), the John D. & Catherine T. MacArthur Foundation; Scherling-Plaugh Award (1999), American Society of Biochemistry and Molecular Biology; Distinguished Alumni Award (2006), Purdue University. Fellow of AAAS (2011). Dr. Guan studies signaling mechanisms of organ size control and tumorigenesis, particularly focusing on the mTOR and Hippo pathways. He has published over 200 peer-reviewed papers.

Dean of the USC Dana and David Dornsife College of Letters, Arts, and Sciences; Professor of Biological Sciences, Neurology, and Physiology, Molecular and Computational Biology, University of Southern California

Nancy B. Spinner, PhD, FACMG
Evelyn Willing Bromley Endowed Chair in Pathology
The Children's Hospital of Philadelphia
Scientific Director, Division of Genomic Diagnostics
Professor of Pathology and Laboratory Medicine
Perelman School of Medicine University of Pennsylvania

“New Developments in HPV-Host Interactions: Consequences for Treatment” at noon at Aresty Auditorium.

Monday, Nov 26th, 2012
Aresty Auditorium, NRT-LG
Harlyne J. Norris Cancer Research Tower
1450 Biggy Street, Lower Ground
12 - 1pm

Aresty Auditorium, 12-1:00pm

“Brain, Hormone, and Appetitive Responses to High- Reward Foods: Implications for Obesity and Disease.”
Abstract:
Obesity is a worldwide epidemic resulting in part from the ubiquity of high-calorie foods and food images. Our group is interested in the neuroendocrine regulation of appetite and feeding behavior and its sensitivity to environmental food exposure. We are taking a multifaceted approach to examine this problem. One aspect of our research addresses the effects of consumption of two sugars, glucose and fructose, on satiety regulating hormones and brain pathways that regulate food intake. We have found that glucose but not fructose consumption: a) decreases regional cerebral blood flow (a marker of neuronal activity) in the hypothalamus, insula and striatum, brain regions that regulate appetite and reward, b) produces a greater rise in systemic levels of the satiety-signaling hormones, insulin and GLP-1, and c) results in increased ratings of satiety in normal-weight volunteers. These findings offer a potential neuroendocrine mechanism for the association between recent increases in fructose consumption and the obesity epidemic.

In another series of neuroimaging experiments, we investigated how circulating levels of glucose, the primary fuel source for the brain, influence brain regions that regulate the motivation to consume high-calorie foods in obese and normal-weight volunteers. We found that obese individuals exhibited an enhanced sensitivity of the appetite and reward circuitry to high-calorie food cues under mild hypoglycemia, and lacked activation of the prefrontal cortex, the brain’s inhibitory control center, under normal glucose conditions. This imbalance between appetite and reward activation and cortical inhibitory control may make obese people more susceptible to overeating behavior.

Abstract:
Our lab uses the skin as a model system to study the molecular and cell biological regulation of skin and hair morphogenesis and malignancy. We have taken advantage of reprogramming technology to develop human iPS-derived keratinocytes and are studying the basis of early human ectodermal development. One of the key factors mediating early skin morphogenesis is the lipoprotein growth factor hedgehog, where lack of hedgehog signaling results in the absence of hair. We have found that hedgehog signaling is required in both the epithelial and surrounding mesenchymal niche for distinct functions. Ectopic hedgehog signaling contributes to a variety of human cancers including basal cell carcinomas of the skin. Our mechanistic and clinical studies of the pathway have contributed to the approval of the first hedgehog pathway inhibitor and the development of next generation pathway inhibitors for skin cancers.

Biography:
Dr. Oro trained in the medical scientist program at the Salk Institute in Ron Evans lab, working on functions of novel orphan nuclear receptors in model systems. During Dermatology residency/fellowship in Matthew Scott’s lab at Stanford, he helped solidify the link between the hedgehog pathway and cancer. In his own lab in the Program in Epithelial Biology at Stanford, Dr. Oro uses skin stem cells to understand mechanisms of tissue regeneration and carcinogenesis. He has a longstanding interest in the mechanisms of hedgehog signaling in hair follicle regeneration, and in the pathogenesis of the most common human tumor, basal cell carcinoma of the skin. He has continued his interest in the mechanisms of human skin development and early ectodermal differentiation by developing in vitro human skin differentiation from embryonic stem cells with the goal of producing corrected human epidermal sheets from patient-specific iPS cells.