Our laboratory studies the basic cellular and molecular mechanisms underlying complex neuropsychiatric diseases, such as bipolar disorder and schizophrenia, as well as general mechanisms of plasma membrane organization in polarized cells.

In the vertebrate nervous system, a large 480 kDa splice variant of ankyrin-G is responsible for the formation of the axon initial segment and nodes of Ranvier, critical sites of clustered voltage-gated sodium channels that are necessary for normal neuronal signaling [1]. A truncating mutation in the giant exon of ankyrin-G causes autism and marked cognitive dysfunction (IQ less than 50) [2]. Importantly, ankyrin-G also has been linked to bipolar disorder in genome-wide association studies [3]. The 480 kDa splice variant of ankyrin-G is necessary for the formation of inhibitory connections in the cortex and hippocampus [4]. Interneurons that release γ-aminobutyric acid (GABA) are a major source of inhibitory signaling in vertebrate nervous systems, and defects in these circuits are strongly associated with neuropsychiatric disorders. Our laboratory examines how human variants affect the formation of inhibitory circuits in mouse models and in samples derived from human patients with the hopes of identifying therapeutic pathways for the restoration of these critical neuronal connections.

Epithelial cells are the most highly represented cell type in the human body and lie at the interface between the body and the outside environment. Epithelia play critical roles in ion homeostasis, absorption and excretion, and protection from microbial invasion. Ankyrin-G and its binding partner beta II-spectrin localize to the lateral membrane of columnar epithelial cells, where loss of either protein impairs cell height and lateral membrane formation [5-9]. Recent work identified the lateral membrane-localized palmitoyltransferases, aspartate-histidine-histidine-cysteine 5 and 8 (DHHC5/8), as the mediators of palmitoylation of ankyrin-G at C70, as silencing of both transferases abolished ankyrin-G palmitoylation, impaired membrane localization of ankyrin-G, and reduced lateral membrane height [5]. Our laboratory is interested in the mechanisms of protein targeting to the lateral membrane and how the palmitoyltransferases, ankyrin-G, and spectrin work together as a team to promote lateral membrane biogenesis.

  1. Jenkins, P.M., N. Kim, S.L. Jones, W.C. Tseng, T.M. Svitkina, et al., Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc Natl Acad Sci U S A, 2015. 112(4): p. 957-64.
  2. Iqbal, Z., G. Vandeweyer, M. van der Voet, A.M. Waryah, M.Y. Zahoor, et al., Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet, 2013. 22(10): p. 1960-70.
  3. Ferreira, M.A., M.C. O’Donovan, Y.A. Meng, I.R. Jones, D.M. Ruderfer, et al., Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet, 2008. 40(9): p. 1056-8.
  4. Tseng, W.C., P.M. Jenkins, M. Tanaka, R. Mooney, and V. Bennett, Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors. Proc Natl Acad Sci U S A, 2015. 112(4): p. 1214-9.
  5.  He, M., K.M. Abdi, and V. Bennett, Ankyrin-G palmitoylation and betaII-spectrin binding to phosphoinositide lipids drive lateral membrane assembly. J Cell Biol, 2014. 206(2): p. 273-88.
  6. Jenkins, P.M., C. Vasavda, J. Hostettler, J.Q. Davis, K. Abdi, et al., E-cadherin polarity is determined by a multifunction motif mediating lateral membrane retention through ankyrin-G and apical-lateral transcytosis through clathrin. J Biol Chem, 2013. 288(20): p. 14018-31.
  7. Kizhatil, K. and V. Bennett, Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G. J Biol Chem, 2004. 279(16): p. 16706-14.
  8. Kizhatil, K., J.Q. Davis, L. Davis, J. Hoffman, B.L. Hogan, et al., Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J Biol Chem, 2007. 282(36): p. 26552-61.
  9. Jenkins PM*, He M*, Bennett V. Dynamic spectrin/ankyrin-G microdomains promote lateral membrane assembly by opposing endocytosis. Sci. Adv. 2015; 1(8):e1500301

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