Biochemistry and Molecular Biology
Penn State Science
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Wendy Hanna-Rose

Wendy Hanna-Rose

Main Content

  • Interim Department Head, Biochemistry and Molecular Biology
  • Associate Professor of Biochemistry and Molecular Biology
  • Department of Biochemistry and Molecular Biology
104D Life Sciences Building
University Park, PA 16802
Email: wxh21@psu.edu
Phone: (814) 865-7904

Research Interests

Molecular Genetics of Metabolism and Development in C. elegans

Wendy Hanna-Rose

 

 

Graduate Programs

BMMB, MCIBS

Research Summary

The overarching goal of the Hanna-Rose lab is to understand how development is genetically programmed and how metabolism supports developmental processes. We use the development of the reproductive structures and neuromuscular system in the nematode  Caenorhabditis elegans as a research model. C. elegans is a simple organism with few cells.  Yet, its development and physiology are sufficiently complex to represent the major mechanisms in animal development and homeostasis. C. elegans has been a valuable model for probing both developmental mechanisms and the impact of metabolism and environment in aging and health, and principles deduced in this system are relevant to higher organisms, including humans.

1. Developmental and physiological roles of NAD+ biosynthetic pathways

Nicotinamide (NAM) and nicotinic acid (NA), which are forms of the essential vitamin B3, are precursors for biosynthesis of nicotinamide adenine dinucleotide (NAD+).  NAD+ is a central molecule in metabolism and a co-substrate for NAD+ consuming enzymes that regulate key biological processes, such as longevity and stress responses.  While the biochemistry of NAD+ biosynthesis from vitamin B3 is well studied, the biological impacts of disruption of this biosynthetic pathway in a multicellular organism are not. We have made the novel discovery that mutation of the first enzyme in the NAM to NAD+ salvage biosynthesis pathway (PNC-1) cause developmental and functional defects in organ systems and necrotic death of specific cells (Figure 1) in C. elegans.  We aim to understand how perturbation of metabolism and / or NAD+ consumer activity during development contributes to the function of organ systems in adulthood and how PNC-1 activity may impact the ability of the organism to respond to cellular stress.

We have tied the lack of NAD+ biosynthesis in the pnc-1 mutant to the developmental phenotypes. Current research is focused on how defects in NAD+ biosynthesis affect muscle and reproductive development.  We are using targeted metabolomics and global metabolomics profiling to discover the metabolic effects of perturbations in NAD+ biosynthesis, and then we apply genetics and pharmacological supplementation experiments to probe the relationship of these changes to developmental phenotypes.

We have tied the accumulation of nicotinamide NAM in the in the pnc-1 mutant to the cell death and neurosensory phenotypes as well as some of the muscle developmental and functional defects. Using similar approaches to above, we have identified pathways targeted by NAM.

2. Inborn errors of purine metabolism

Inborn errors of metabolism are genetic diseases caused by reduced function of metabolic enzymes. We use the organism C. elegans to model syndromes caused by Inborn Errors of Purine Metabolism. We have two goals: to elucidate the molecular mechanisms that cause neuromuscular and reproductive pathologies and to generate ideas for novel therapies. 

Purine nucleotides are monomers that comprise nucleic acids, and they also serve signaling, energy storage, energy transfer, and metabolic roles in cells. Given their vital roles in metabolism, it is surprising that mutations in purine biosynthetic pathways can have specific physiological effects in only one or a few organ systems. Yet, dysfunction of specific purine metabolic enzymes is associated with autistic-like and compulsive behaviors in humans as well as degenerative neuromuscular phenotypes. These molecular mechanisms that cause these phenotypes are mysterious. We are modeling and investigating the disease adenylosuccinate lyase deficiency using RNAi and genetic mutants in C. elegans.

Figure 1.  The uv1 cells swell dramatically and necrose in a pnc-1 mutant animal.

Hanna-Rose figure 1

Selected Publications

  • McReynolds, M R.,Wang W, Holleran LM, and W.  Hanna-Rose. (2017) Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid. The Journal of Biological Chemistry. Accelerated Communication. doi: 10.1074/jbc.C117.795344

  • Upadhyay A, Pisupati A, Jegla T, Crook M, Mickolajczyk KJ, Shorey M, Rohan LE, Billings KA, Rolls MM, Hancock WO and W. Hanna-Rose (2016) Nicotinamide is an endogenous agonist for a C. elegans TRPV OSM-9 and OCR-4 channel. Nature Communications.  7:13135. doi: 10.1038/ncomms13135.

  • Hester J, Hanna-Rose W and F. Diaz.  (2016) Zinc deficiency reduces fertility in C. elegans hermaphrodites and disrupts oogenesis and meiotic progression. Comp Biochem Physiol C Toxicol Pharmacol. 2016 Sep 20. pii: S1532-0456(16)30114-4. doi: 10.1016/j.cbpc.2016.09.006

  • Crook M, Upadhyay A, Ido LJ and Hanna-Rose W. (2016) EGFR Cell Survival Signaling Requires Phosphatidylcholine Biosynthesis. G3 (Bethesda). 2016 Sep 7. pii: g3.116.034850. doi: 10.1534/g3.116.034850.

  • Wang W, McReynolds MR, Goncalves JF, Shu M, Dhondt I, Braeckman BP, Lange SE, Kho K, Detwiler AC, Pacella MJ and W. Hanna-Rose. (2015) Comparative metabolomic profiling reveals that dysregulated glycolysis stemming from lack of salvage NAD+ biosynthesis impairs reproductive development in C. elegans. JBC 290(43):26163-79. doi: 10.1074/jbc.M115.662916.

  • Crook M, McReynolds M.R., Wang W and W. Hanna-Rose. (2014) An NAD+ biosynthetic pathway enzyme functions cell non-autonomously in C. elegans development. Developmental Dynamics 243(8): 955-76 doi: 10.1002/dvdy.24139

  • Zhou K, Rolls MM and W. Hanna-Rose. (2013) A postmitotic function and distinct localization mechanism for centralspindlin at a stable intercellular bridge. Developmental Biology 376(1):13-22

  • Tracy L. Vrablik, Wenqing Wang, Awani Upadhyah and Wendy Hanna-Rose (2011) Muscle type-specific responses to NAD+ salvage biosynthesis promote muscle function in Caenorhabditis elegans. Developmental Biology 359(2): 387-94.

  • JB French, Y. Cen, Tracy L. Vrablik, P Xu, E. Allen, Wendy Hanna-Rose, Anthony A Sauve. (2010) Characterization of nicotinamidases: steady state kinetic parameters, classwide inhibition by nicotinaldehydes, and catalytic mechanism. Biochemistry 49(49):10421-39.

  • Kang Zhou and Wendy Hanna-Rose (2010) Movers and shakers of anchored: Caenorhabditis elegans nuclei achieve it with KASH/ SUN. Dev Dyn. 239(5):1352-64.

  • Tracy L. Vrablik, Li Huang, Stephanie E. Lange and Wendy Hanna-Rose (2009) Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans. Development 136(21):3637-3646.

  • Kang Zhou, Melissa M. Rolls, David H. Hall, Christian J. Malone and Wendy Hanna-Rose (2009) A ZYG-12-dynein interaction at the nuclear envelope defines cytoskeletal architecture in the C. elegans gonad. Journal of Cell Biology 186(2) 229-41.

  • Kathleen A. Estes and Wendy Hanna-Rose (2009) The anchor cell initiates dorsal lumen formation during C. elegans vulval tubulogenesis. Developmental Biology 328(2):297-304.

  • Nicholas N. Lyssenko, Wendy Hanna-Rose, and Robert A. Schlegel. (2007) A cognate putative nuclear localization signal effects strong nuclear localization of a GFP reporter and facilitates gene expression studies in C. elegans. BioTechniques 43(5):596-600.

  • Kathleen A. Estes, Rasika Kalamegham, and Wendy Hanna-Rose. (2007) Membrane localization of the NlpC/P60 family protein EGL-26 correlates with regulation of vulval cell morphogenesis in C. elegans". Developmental Biology 308(1):196-205.

  • Li Huang and Wendy Hanna-Rose. (2006) EGF signaling overcomes a uterine cell death associated with temporal mis-coordination of organogenesis within the C. elegans egg-laying apparatus. Developmental Biology 300(2):599-611.