Grant R. MacGregor, D.Phil.

  • Mouse Reproduction, Development and Homeostasis
  • Functions of FNDC3 proteins
  • Improved Mouse Models of Late Onset Alzheimer’s Disease

Since 1993 the MacGregor laboratory has investigated the molecular basis for mammalian reproduction and development, using the mouse as a model genetic system. With our collaborators, these studies have made new contributions to our understanding of mechanisms of germline development, skeletogenesis, programmed cell death, post-translational modification of microtubules, and mitochondrial genetics and biology.

Functions for FNDC3 proteins

A current research goal is to identify the roles of the novel Fndc3 gene family in mammalian reproduction, development and homeostasis, and to understand how FNDC3 proteins function. We do so because mice with altered Fndc3 function display pathology found in several common human health conditions that have significant societal and economic impact. These include bone fragility, infertility, lactational insufficiency, neonatal acute respiratory distress, non-alcoholic fatty liver disease, obesity, and abnormal skeletogenesis. FNDC3B is also frequently amplified and over-expressed in both liver and brain cancer, and knockdown of FNDC3B can inhibit metastasis in vivo. We predict that understanding how FNDC3 proteins function will provide insight into mechanisms that contribute to human birth defects and adult disease.

Improved Mouse Models of Late Onset Alzheimer’s Disease

The MacGregor lab is part of the UCI component of the NIA / NIH funded Model Organism Development & Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) program. The goals of MODEL-AD are to develop and validate improved mouse models that can be used to investigate mechanisms of late-onset Alzheimer’s Disease (LOAD). Using open-science practices, all data and mouse models generated by MODEL-AD are available for use by both academia and for-profit industry without restrictions.

Recent and Selected Publications

  • David Baglietto-Vargas D, Forner S, Cai L, Martini AC, Trujillo-Estrada L, Swarup V, Nguyen MMT, Huynh KD, Javonillo DI, Tran KM, Phan J, Jiang S, Kramár EA,  Nuñez-Diaz C, Balderrama-Gutierrez G, Garcia F, Childs J, Rodriguez-Ortiz CJ,  Garcia-Leon JA, Kitazawa M, Shahnawaz M, Matheos DP, Ma X, Da Cunha C, Walls KC, Ager RR, Soto C, Gutierrez A, Moreno-Gonzalez I, Mortazavi A, Tenner AJ, MacGregor GR, Wood M, Green KN, LaFerla FM. (2021) A humanized Ab knock-in mouse strain: a platform model to study late-onset Alzheimer’s Disease. Nature Communications, in press.

  • Das A, Zhu B, Xie Y, Zeng L, Pham A, Neumann J, Safrina O, Benavides D, MacGregor GR, Schutte S, Hunt R, and O’Dowd  DK. (2021) Interneuron dysfunction in a new mouse model of SCN1A GEFS+. eNeuro, in press.

  • Y-H Lin H, Chen Y, Chen YH, Ta AP, Lee HC, MacGregor GR, Vaziri ND, Wang PH. (2020) Tubular mitochondrial AKT1 is activated during ischemia reperfusion injury and has a critical role in predisposition to chronic kidney disease. Kidney Int. Dec 11;. doi: 10.1016/j.kint.2020.10.038.

  • Oblak AL, Forner S, Territo PR, Sasner M, Carter GW, Howell GR, Sukoff-Rizzo SJ, Logsdon BA, Mangravite LM, Mortazavi A, Baglietto-Vargas D, Green KN, MacGregor GR, Wood MA, Tenner AJ, LaFerla FM, Lamb BT; and The MODEL‐AD; Consortium. (2020) Model Organism development and evaluation for late-onset Alzheimer’s disease: MODEL-AD. Alzheimers Dement (N Y). 2020 Nov 23;6(1):e12110. doi: 10.1002/trc2.12110. eCollection 2020.

  • Syed A, Lukacsovich T, Pomeroy M, Bardwell AJ, Decker GT, Waymire KG, Purcell J, Huang W, Gui J, Padilla EM, Park C, Paul A, Pham TBT, Rodriguez Y, Wei S, Worthge S, Zebarjedi R, Zhang B, Bardwell L, Marsh JL, MacGregor GR. (2019) Miles to go (mtgo) encodes FNDC3 proteins that interact with the chaperonin subunit CCT3 and are required for NMJ branching and growth in Drosophila. Dev Biol. 445(1):37-53.

  • Fonseca MI, Chu S-H, Hernandez MX, Fang MJ, Modarresi L, Selvan P, MacGregor GR and Tenner AJ (2017) Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. Journal of Neuroinflammation 14: 48.

  • Kokoszka JE, Waymire KG, Flierl A, MacGregor GR, and Wallace DC (2016) The role of mitochondrial adenine nucleotide translocator isoforms 2 in cardiac development and noncompaction. Biochemica et Biopyhsica Acta 1857: 1203-1212.

  • Reyes de Mochel NS, Luong M, Chiang M, Javier AL, Luu E, Fujimori T, MacGregor GR, Cinquin O and Cho KWY (2015) BMP signaling is required for cell cleavage in pre-implantation stage mouse embryos. Dev. Biol. 397:45-55.

  • Lin CS, Sharpley MS, Fan WW, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, McManus MJ, Pan BX, Gil DW, MacGregor GR, Wallace DC (2012) Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc. Natl. Acad. Sci. (USA) 109, 20065 – 20070.

  • Sharpley MS, Marciniak C, Eckel-Mahan K, McManus M, Waymire KG, Crimi M, Lin CS, Masubuchi S, Friend N, Koike M, Chalkia M, MacGregor GR, Sassone-Corsi P and Wallace DC (2012) Maternal inheritance of two different mouse mtDNAs is genetically stable and results in altered behavior and cognition.  Cell 151, 333-343.

  • Navarro SJ, Trinh T, Lucas CA, Ross AJ, Waymire KG, MacGregor GR (2012) The C57BL/6J mouse stain background modifies the effect of a mutation in Bcl2l2. G3 : Genes, Genomes, Genetics 2, 99-102.

  • Ikegami K, Horigome, D, Mukai, M, Livnat, I, MacGregor, GR, and Setou, M (2008) TTLL10 is a protein polylgycylase that can modify nucleosome assembly protein 1 FEBS Lett. 582, 1129-1134.

  • Fan W-W, Waymire KG, Narula N, Li, P, Rocher C, Coskun PE, Vannan MA, Narula J, MacGregor GR, Wallace D.C. (2008) A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958 – 962.

  • Ikegami K, Heier RL, Taruishi M, Takagi H, Mukai M, Shimma S, Taira S, Hatanaka K, Morone N, Yao I, Campbell PK, Yuasa S, Janke C, MacGregor GR*, and Setou M* (2007) Loss of Alpha Tubulin Polyglutamylation in ROSA22 Mice is Associated with Abnormal Targeting of KIF1A and Modulated Synaptic Function (*co-corresponding authors) Proc. Natl. Acad. Sci. (USA) 104, p3213 – 3218.

  • Obholz KL, Akopyan AA, Waymire KG, MacGregor GR (2006) FNDC3A is required for adhesion between spermatids and Sertoli cell in mice. Developmental Biology 298, 498-513.

  • Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai JY, Jones D.P., MacGregor GR, and Wallace DC (2004)  The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore.  Nature, 427, 461-465.

  • Campbell PK, Waymire KG, Heier RL, Scharer C, Day DE, Reimann H, Jaje JM, Friedrich GA, Burmeister M, Russell LD, Bartness TJ, Young LJ, Zimmer M, Jenne DE and MacGregor GR (2002) Mutation of a novel gene results in abnormal development of spermatid flagellum, loss of inter-male aggression and reduced body fat in mice. Genetics, 162, 307-320.

  • Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsakopoulou T, Roth KA, Ross AJ, MacGregor GR, Thompson CB and Korsmeyer SJ (2001) Pro-apoptotic BAX and BAK are essential for mitochondrial dysfunction and death following diverse apoptotic signals. Science 292, 727-730.

  • Zong W-X, Lindsten T, Ross AJ, MacGregor GR and Thompson CB (2001) BH3-only proteins that bind pro-survival BCL2 family members fail to induce apoptosis in the absence of BAX and BAK. Genes & Dev. 15, 1481-1486.

  • Lindsten T, Ross AJ, Gottlieb-King A, Zong W-X, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar PL, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G Korsmeyer SJ, MacGregor GR and Thompson CB (2000) The combined functions of the pro-apoptotic BCL2 family members BAK and BAX are essential for the normal development of multiple tissues. Molecular Cell 6, 1389-1399.

  • Abe K, Ko MSH and MacGregor GR (1998) A systematic molecular genetic approach to study mammalian germ line development. J. Dev Biol., 42,1051-1066.

  • Ross A, Waymire KG, Moss JE, Parlow AF, Skinner MK, Russell LD and MacGregor GR (1998) Testicular degeneration in Bclw deficient mice. Nature Genetics, 18, 251-256.

  • Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR and Wallace DC (1997) A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart / skeletal muscle isoform of the adenine nucleotide translocator.  Nature Genetics 16, 226-234.

  • Waymire KG, Jaje JM, Mahuren D, Guilarte T, Coburn SP and MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nature Genetics, 11, 45-51.

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