Publications

all Publications

Kang, S.J., Liu, S., Kim, J.H., Kim, D.I., Oh, T.G., Peng, J., Ye, M., Lee, K.F., Evans, R.M., Goulding, M., Han, S. Thalamic CGRP neurons define a spinothalamic pathway for affective pain. (2025) Proceedings of the National Academy of Sciences of the United States of America. 122(28):e2505889122. DOI: 10.1073/pnas.2505889122

+ expand abstract

Zhou, J., Zhang, Z., Wu, M., Liu, H., Pang, Y., Bartlett, A., Peng, Z., Ding, W., Rivkin, A., Lagos, W.N., Williams, E., Lee, C.T., Miyazaki, P.A., Aldridge, A., Zeng, Q., Salinda, J.L.A., Claffey, N., Liem, M., Fitzpatrick, C., Boggeman, L., Yao, Z., Smith, K.A., Tasic, B., Altshul, J., Kenworthy, M.A., Valadon, C., Nery, J.R., Castanon, R.G., Patne, N.S., Vu, M., Rashid, M., Jacobs, M., Ito, T., Osteen, J., Emerson, N., Lee, J., Cho, S., Rink, J., Huang, H.H., Pinto-Duartec, A., Dominguez, B., Smith, J.B., O’Connor, C., Zeng, H., Chen, S., Lee, K.F., Mukamel, E.A., Jin, X., Margarita Behrens, M., Ecker, J.R., Callaway, E.M. Brain-wide correspondence of neuronal epigenomics and distant projections. (2023) Nature. 624(7991):355-365. DOI: 10.1038/s41586-023-06823-w

+ expand abstract

Kang, S.J., Liu, S., Ye, M., Kim, D.I., Pao, G.M., Copits, B.A., Roberts, B.Z., Lee, K.F., Bruchas, M.R., Han, S. A central alarm system that gates multi-sensory innate threat cues to the amygdala. (2022) Cell Reports. 40(7):111222. DOI: 10.1016/j.celrep.2022.111222

+ expand abstract

Jovanovic, V., Fishbein, A.R., de la Mothe, L., Lee, K.F., Miller, C.T. Behavioral context affects social signal representations within single primate prefrontal cortex neurons. (2022) Neuron. DOI: 10.1016/j.neuron.2022.01.020

+ expand abstract

Zhang, Z., Zhou, J., Tan, P., Pang, Y., Rivkin, A.C., Kirchgessner, M.A., Williams, E., Lee, C.T., Liu, H., Franklin, A.D., Miyazaki, P.A., Bartlett, A., Aldridge, A.I., Vu, M., Boggeman, L., Fitzpatrick, C., Nery, J.R., Castanon, R.G., Rashid, M., Jacobs, M.W., Ito-Cole, T., O’Connor, C., Pinto-Duartec, A., Dominguez, B., Smith, J.B., Niu, S.Y., Lee, K.F., Jin, X., Mukamel, E.A., Behrens, M.M., Ecker, J.R., Callaway, E.M. Epigenomic diversity of cortical projection neurons in the mouse brain. (2021) Nature. 598(7879):167-173. DOI: 10.1038/s41586-021-03223-w

+ expand abstract

Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results showed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. On the basis of their epigenomes, intra-telencephalic cells that project to different cortical targets could be further distinguished, and some layer 5 neurons that project to extra-telencephalic targets (L5 ET) formed separate clusters that aligned with their axonal projections. Such separation varied between cortical areas, which suggests that there are area-specific differences in L5 ET subtypes, which were further validated by anatomical studies. Notably, a population of cortico-cortical projection neurons clustered with L5 ET rather than intra-telencephalic neurons, which suggests that a population of L5 ET cortical neurons projects to both targets. We verified the existence of these neurons by dual retrograde labelling and anterograde tracing of cortico-cortical projection neurons, which revealed axon terminals in extra-telencephalic targets including the thalamus, superior colliculus and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.

Liu, S., Kim, D.I., Oh, T.G., Pao, G.M., Kim, J.H., Palmiter, R.D., Banghart, M.R., Lee, K.F., Evans, R.M., Han, S. Neural basis of opioid-induced respiratory depression and its rescue. (2021) Proceedings of the National Academy of Sciences of the United States of America. 118(23). DOI: 10.1073/pnas.2022134118

+ expand abstract

Lee, E.Y., Chan, L.C., Wang, H., Lieng, J., Hung, M., Srinivasan, Y., Wang, J., Waschek, J.A., Ferguson, A.L., Lee, K.F., Yount, N.Y., Yeaman, M.R., Wong, G.C.L. PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain. (2021) Proceedings of the National Academy of Sciences of the United States of America. 118(1). DOI: 10.1073/pnas.1917623117

+ expand abstract

Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of or infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation.

Liu, Y., Sugiura, Y., Chen, F., Lee, K.F., Ye, Q., Lin, W. Blocking skeletal muscle DHPRs/Ryr1 prevents neuromuscular synapse loss in mutant mice deficient in type III Neuregulin 1 (CRD-Nrg1). (2019) PLOS Genetics. 15(3):e1007857. DOI: 10.1371/journal.pgen.1007857

+ expand abstract

Schwann cells are integral components of vertebrate neuromuscular synapses; in their absence, pre-synaptic nerve terminals withdraw from post-synaptic muscles, leading to muscle denervation and synapse loss at the developing neuromuscular junction (NMJ). Here, we report a rescue of muscle denervation and neuromuscular synapses loss in type III Neuregulin 1 mutant mice (CRD-Nrg1-/-), which lack Schwann cells. We found that muscle denervation and neuromuscular synapse loss were prevented in CRD-Nrg1-/-mice when presynaptic activity was blocked by ablating a specific gene, such as Snap25 (synaptosomal-associated 25 kDa protein) or Chat (choline acetyltransferase). Further, these effects were mediated by a pathway that requires postsynaptic acetylcholine receptors (AChRs), because ablating Chrna1 (acetylcholine receptor α1 subunit), which encodes muscle-specific AChRs in CRD-Nrg1-/-mice also rescued muscle denervation. Moreover, genetically ablating muscle dihydropyridine receptor (DHPR) β1 subunit (Cacnb1) or ryanodine receptor 1 (Ryr1) also rescued muscle denervation and neuromuscular synapse loss in CRD-Nrg1-/-mice. Thus, these genetic manipulations follow a pathway-from presynaptic to postsynaptic, and, ultimately to muscle activity mediated by DHPRs and Ryr1. Importantly, electrophysiological analyses reveal robust synaptic activity in the rescued, Schwann-cell deficient NMJs in CRD-Nrg1-/-Cacnb1-/-or CRD-Nrg1-/-Ryr1-/-mutant mice. Thus, a blockade of synaptic activity, although sufficient, is not necessary to preserve NMJs that lack Schwann cells. Instead, a blockade of muscle activity mediated by DHRPs and Ryr1 is both necessary and sufficient for preserving NMJs that lack Schwann cells. These findings suggest that muscle activity mediated by DHPRs/Ryr1 may destabilize developing NMJs and that Schwann cells play crucial roles in counteracting such a destabilizing activity to preserve neuromuscular synapses during development.

Gould, T.W., Dominguez, B., de Winter, F., Yeo, G.W., Liu, P., Sundararaman, B., Stark, T., Vu, A., Degen, J.L., Lin, W., Lee, K.F. Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal. (2019) PLOS Genetics. 15(3):e1007948. DOI: 10.1371/journal.pgen.1007948

+ expand abstract

Yoon, Y.S., Tsai, W.W., Van de Velde, S., Chen, Z., Lee, K.F., Morgan, D.A., Rahmouni, K., Matsumura, S., Wiater, E., Song, Y., Montminy, M. cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis. (2018) Proceedings of the National Academy of Sciences of the United States of America. DOI: 10.1073/pnas.1805257115

+ expand abstract

Chen, Z., Donnelly, C.R., Dominguez, B., Harada, Y., Lin, W., Halim, A.S., Bengoechea, T.G., Pierchala, B.A., Lee, K.F. p75 Is Required for the Establishment of Postnatal Sensory Neuron Diversity by Potentiating Ret Signaling. (2017) Cell Reports. 21(3):707-720. DOI: 10.1016/j.celrep.2017.09.037

+ expand abstract

Hirai, M., Arita, Y., McGlade, C.J., Lee, K.F., Chen, J., Evans, S.M. Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation. (2017) Journal of Clinical Investigation. 127(2):569-582. DOI: 10.1172/JCI91081

+ expand abstract

Xu, J., de Winter, F., Farrokhi, C., Rockenstein, E., Mante, M., Adame, A., Cook, J., Jin, X., Masliah, E., Lee, K.F. Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model. (2016) Scientific Reports. 6:31692. DOI: 10.1038/srep31692

+ expand abstract

Chu, Q., Diedrich, J.K., Vaughan, J.M., Donaldson, C.J., Nunn, M.F., Lee, K.F., Saghatelian, A. HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective. (2016) Journal of the American Chemical Society. 138(30):9473-8. DOI: 10.1021/jacs.6b03463

+ expand abstract

Mo, A.H., Landon, P.B., Gomez, K.S., Kang, H., Lee, J., Zhang, C., Janetanakit, W., Sant, V., Lu, T., Colburn, D.A., Akkiraju, S., Dossou, S., Cao, Y., Lee, K.F., Varghese, S., Glinsky, G., Lal, R. Magnetically-responsive silica-gold nanobowls for targeted delivery and SERS-based sensing. (2016) Nanoscale. 8(23):11840-50. DOI: 10.1039/c6nr02445a

+ expand abstract

Amin, N.D., Bai, G., Klug, J.R., Bonanomi, D., Pankratz, M.T., Gifford, W.D., Hinckley, C.A., Sternfeld, M.J., Driscoll, S.P., Dominguez, B., Lee, K.F., Jin, X., Pfaff, S.L. Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. (2015) Science. 350(6267):1525-9. DOI: 10.1126/science.aad2509

+ expand abstract

Izpisua Belmonte, J.C., Callaway, E.M., Caddick, S.J., Churchland, P., Feng, G., Homanics, G.E., Lee, K.F., Leopold, D.A., Miller, C.T., Mitchell, J.F., Mitalipov, S., Moutri, A.R., Movshon, J.A., Okano, H., Reynolds, J.H., Ringach, D., Sejnowski, T.J., Silva, A.C., Strick, P.L., Wu, J., Zhang, F. Brains, genes, and primates. (2015) Neuron. 86(3):617-31. DOI: 10.1016/j.neuron.2015.03.021

+ expand abstract

Vilar, M., Sung, T.C., Chen, Z., García-Carpio, I., Fernandez, E.M., Xu, J., Riek, R., Lee, K.F. Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action. (2014) PLOS Biology. 12(8):e1001918. DOI: 10.1371/journal.pbio.1001918

+ expand abstract

Large, M.J., Wetendorf, M., Lanz, R.B., Hartig, S.M., Creighton, C.J., Mancini, M.A., Kovanci, E., Lee, K.F., Threadgill, D.W., Lydon, J.P., Jeong, J.W., DeMayo, F.J. The epidermal growth factor receptor critically regulates endometrial function during early pregnancy. (2014) PLOS Genetics. 10(6):e1004451. DOI: 10.1371/journal.pgen.1004451

+ expand abstract

Infertility and adverse gynecological outcomes such as preeclampsia and miscarriage represent significant female reproductive health concerns. The spatiotemporal expression of growth factors indicates that they play an important role in pregnancy. The goal of this study is to define the role of the ERBB family of growth factor receptors in endometrial function. Using conditional ablation in mice and siRNA in primary human endometrial stromal cells, we identified the epidermal growth factor receptor (Egfr) to be critical for endometrial function during early pregnancy. While ablation of Her2 or Erbb3 led to only a modest reduction in litter size, mice lacking Egfr expression are severely subfertile. Pregnancy demise occurred shortly after blastocyst implantation due to defects in decidualization including decreased proliferation, cell survival, differentiation and target gene expression. To place Egfr in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of Egfr, wingless-related MMTV integration site 4 (Wnt4) or boneless morphogenic protein 2 (Bmp2); revealing that not only are Bmp2 and Wnt4 key downstream effectors of Egfr, but they also regulate distinct physiological functions. In primary human endometrial stromal cells, marker gene expression, a novel high content image-based approach and phosphokinase array analysis were used to demonstrate that EGFR is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries WNK1 and AKT1S1, members identified in the kinase array and previously unreported to play a role in the endometrium, also attenuate decidualization. These results demonstrate that EGFR plays an integral role in establishing the cellular context necessary for successful pregnancy via the activation of intricate signaling and transcriptional networks, thereby providing valuable insight into potential therapeutic targets.

Sung, T.C., Chen, Z., Thuret, S., Vilar, M., Gage, F.H., Riek, R., Lee, K.F. P45 forms a complex with FADD and promotes neuronal cell survival following spinal cord injury. (2013) PLOS One. 8(7):e69286. DOI: 10.1371/journal.pone.0069286

+ expand abstract

Seidel, S., Bruce, J., Leblanc, M., Lee, K.F., Fan, H., Ahlquist, P., Young, J.A. ZASC1 knockout mice exhibit an early bone marrow-specific defect in murine leukemia virus replication. (2013) Virology Journal. 10:130. DOI: 10.1186/1743-422X-10-130

+ expand abstract

Wei, P.C., Hsieh, Y.H., Su, M.I., Jiang, X., Hsu, P.H., Lo, W.T., Weng, J.Y., Jeng, Y.M., Wang, J.M., Chen, P.L., Chang, Y.C., Lee, K.F., Tsai, M.D., Shew, J.Y., Lee, W.H. Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease. (2012) Molecular Cell. 48(5):747-59. DOI: 10.1016/j.molcel.2012.10.007

+ expand abstract

Morello, C.S., Kraynyak, K.A., Levinson, M.S., Chen, Z., Lee, K.F., Spector, D.H. Inactivated HSV-2 in MPL/alum adjuvant provides nearly complete protection against genital infection and shedding following long term challenge and rechallenge. (2012) Vaccine. 30(46):6541-6550. DOI: 10.1016/j.vaccine.2012.08.049

+ expand abstract

Montminy, M., Lee, K.F., Rivier, J.E., Rivier, C., Reichlin, S. Wylie Vale: neuroendocrine master. (2012) Proceedings of the National Academy of Sciences of the United States of America. 109(10):3604-5. DOI: 10.1073/pnas.1201696109

Yang, J., Dominguez, B., de Winter, F., Gould, T.W., Eriksson, J.E., Lee, K.F. Nestin negatively regulates postsynaptic differentiation of the neuromuscular synapse. (2011) Nature Neuroscience. 14(3):324-30. DOI: 10.1038/nn.2747

+ expand abstract

An, M.C., Lin, W., Yang, J., Dominguez, B., Padgett, D., Sugiura, Y., Aryal, P., Gould, T.W., Oppenheim, R.W., Hester, M.E., Kaspar, B.K., Ko, C.P., Lee, K.F. Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. (2010) Proceedings of the National Academy of Sciences of the United States of America. 107(23):10702-7. DOI: 10.1073/pnas.1004956107

+ expand abstract

Bengoechea, T.G., Chen, Z., O’Leary, D.A., O’Leary, D., Masliah, E., Lee, K.F. p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer’s disease mouse model. (2009) Proceedings of the National Academy of Sciences of the United States of America. 106(19):7870-5. DOI: 10.1073/pnas.0901533106

+ expand abstract

Lim, Y.S., McLaughlin, T., Sung, T.C., Santiago, A., Lee, K.F., O’Leary, D.D. p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. (2008) Neuron. 59(5):746-58. DOI: 10.1016/j.neuron.2008.07.032

+ expand abstract

Wang, W., Takimoto, J.K., Louie, G.V., Baiga, T.J., Noel, J.P., Lee, K.F., Slesinger, P.A., Wang, L. Genetically encoding unnatural amino acids for cellular and neuronal studies. (2007) Nature Neuroscience. 10(8):1063-72. DOI: 10.1038/nn1932

+ expand abstract

Rissman, R.A., Lee, K.F., Vale, W., Sawchenko, P.E. Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation. (2007) Journal of Neuroscience. 27(24):6552-62. DOI: 10.1523/JNEUROSCI.5173-06.2007

+ expand abstract

Li, C., Chen, P., Vaughan, J., Lee, K.F., Vale, W. Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. (2007) Proceedings of the National Academy of Sciences of the United States of America. 104(10):4206-11. DOI: 10.1073/pnas.0611641104

+ expand abstract

Chen, A., Brar, B., Choi, C.S., Rousso, D., Vaughan, J., Kuperman, Y., Kim, S.N., Donaldson, C., Smith, S.M., Jamieson, P., Li, C., Nagy, T.R., Shulman, G.I., Lee, K.F., Vale, W. Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle. (2006) Proceedings of the National Academy of Sciences of the United States of America. 103(44):16580-5. DOI: 10.1073/pnas.0607337103

+ expand abstract

Negro, A., Brar, B.K., Gu, Y., Peterson, K.L., Vale, W., Lee, K.F. erbB2 is required for G protein-coupled receptor signaling in the heart. (2006) Proceedings of the National Academy of Sciences of the United States of America. 103(43):15889-93. DOI: 10.1073/pnas.0607499103

+ expand abstract

Chen, A., Zorrilla, E., Smith, S., Rousso, D., Levy, C., Vaughan, J., Donaldson, C., Roberts, A., Lee, K.F., Vale, W. Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior. (2006) Journal of Neuroscience. 26(20):5500-10. DOI: 10.1523/JNEUROSCI.3955-05.2006

+ expand abstract

Morris, J.K., Maklad, A., Hansen, L.A., Feng, F., Sorensen, C., Lee, K.F., Macklin, W.B., Fritzsch, B. A disorganized innervation of the inner ear persists in the absence of ErbB2. (2006) Brain Research. 1091(1):186-99. DOI: 10.1016/j.brainres.2006.02.090

+ expand abstract

Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E.P., Gage, F.H., Lee, K.F. Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. (2005) Neuron. 46(4):569-79. DOI: 10.1016/j.neuron.2005.04.002

+ expand abstract

Myers, C.P., Lewcock, J.W., Hanson, M.G., Gosgnach, S., Aimone, J.B., Gage, F.H., Lee, K.F., Landmesser, L.T., Pfaff, S.L. Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits. (2005) Neuron. 46(1):37-49. DOI: 10.1016/j.neuron.2005.02.022

+ expand abstract

Wang, P., Yang, G., Mosier, D.R., Chang, P., Zaidi, T., Gong, Y.D., Zhao, N.M., Dominguez, B., Lee, K.F., Gan, W.B., Zheng, H. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. (2005) Journal of Neuroscience. 25(5):1219-25. DOI: 10.1523/JNEUROSCI.4660-04.2005

+ expand abstract

Jackson-Fisher, A.J., Bellinger, G., Ramabhadran, R., Morris, J.K., Lee, K.F., Stern, D.F. ErbB2 is required for ductal morphogenesis of the mammary gland. (2004) Proceedings of the National Academy of Sciences of the United States of America. 101(49):17138-43. DOI: 10.1073/pnas.0407057101

+ expand abstract

Joseph, N.M., Mukouyama, Y.S., Mosher, J.T., Jaegle, M., Crone, S.A., Dormand, E.L., Lee, K.F., Meijer, D., Anderson, D.J., Morrison, S.J. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. (2004) Development. 131(22):5599-612. DOI: 10.1242/dev.01429

+ expand abstract

Negro, A., Brar, B.K., Lee, K.F. Essential roles of Her2/erbB2 in cardiac development and function. (2004) Recent progress in Hormone Research. 59:1-12.

+ expand abstract

The tyrosine kinase receptor erbB2, also known in humans as Her2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family, which also includes erbB3 and erbB4. The erbBs were discovered in an avian erythroblastosis tumor virus and exhibited similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2 is highly expressed in many cancer types. Its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. ErbB receptors bind to a family of growth factors, termed neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4 and include multiple isoforms. ErbB2/Her2 is an orphan receptor that does not bind ligand alone but heterodimerizes with the other erbB receptors for NRG signaling. ErbB2 is expressed in multiple neuronal and non-neuronal tissues in embryos and adult animals, including the heart. Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die before embryonic day (E) 11. To study its role at later stages of development, we generated a transgenic mouse line that specifically expresses the rat erbB2 cDNA in the heart under the control of the cardiac-specific alpha-myosin heavy chain promoter. When crossed into the null background, the expression of the rat erbB2 cDNA rescued the cardiac phenotype in the erbB2-null mutant mice that survive until birth but display an absence of Schwann cells and a severe loss of both motor and spinal sensory neurons. To study the role of erbB2 in the adult heart, we generated conditional mutant mice carrying a cardiac-restricted deletion of erbB2. These erbB2 conditional mutants exhibited multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Interestingly, treatment of breast cancers overexpressing erbB2 with Herceptin (Trastuzumab), a humanized monoclonal antibody specific to the extracellular domain of erbB2, results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. We found that erbB2-deficient cardiac myocytes are more susceptible to anthracycline-induced cytotoxicity. These results suggest that erbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. These lines of mice provide models with which to elucidate the molecular and cellular mechanisms by which erbB2 signaling regulates cardiac functions. These mice also will provide important information for devising strategies to mitigate the cardiotoxic effects of Herceptin treatment, allowing for the potential expanded use of this drug to treat all cancers overexpressing erbB2.

Lin, S.C., Lee, K.F., Nikitin, A.Y., Hilsenbeck, S.G., Cardiff, R.D., Li, A., Kang, K.W., Frank, S.A., Lee, W.H., Lee, E.Y. Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis. (2004) Cancer Research. 64(10):3525-32. DOI: 10.1158/0008-5472.CAN-03-3524

+ expand abstract

Bale, T.L., Hoshijima, M., Gu, Y., Dalton, N., Anderson, K.R., Lee, K.F., Rivier, J., Chien, K.R., Vale, W.W., Peterson, K.L. The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure. (2004) Proceedings of the National Academy of Sciences of the United States of America. 101(10):3697-702. DOI: 10.1073/pnas.0307324101

+ expand abstract

Brar, B.K., Jonassen, A.K., Egorina, E.M., Chen, A., Negro, A., Perrin, M.H., Mjøs, O.D., Latchman, D.S., Lee, K.F., Vale, W. Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine (2004) Endocrinology. 145(1):24-35; discussion 21-3. DOI: 10.1210/en.2003-0689

+ expand abstract

Bale, T.L., Anderson, K.R., Roberts, A.J., Lee, K.F., Nagy, T.R., Vale, W.W. Corticotropin-releasing factor receptor-2-deficient mice display abnormal homeostatic responses to challenges of increased dietary fat and cold. (2003) Endocrinology. 144(6):2580-7. DOI: 10.1210/en.2002-0091

+ expand abstract

Zhao, X., Ueba, T., Christie, B.R., Barkho, B., McConnell, M.J., Nakashima, K., Lein, E.S., Eadie, B.D., Willhoite, A.R., Muotri, A.R., Summers, R.G., Chun, J., Lee, K.F., Gage, F.H. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. (2003) Proceedings of the National Academy of Sciences of the United States of America. 100(11):6777-82. DOI: 10.1073/pnas.1131928100

+ expand abstract

Brandon, E.P., Lin, W., D’Amour, K.A., Pizzo, D.P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C.P., Thal, L.J., Gage, F.H., Lee, K.F. Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. (2003) Journal of Neuroscience. 23(2):539-49.

+ expand abstract

Crone, S.A., Lee, K.F. The bound leading the bound: target-derived receptors act as guidance cues. (2002) Neuron. 36(3):333-5.

+ expand abstract

Crone, S.A., Lee, K.F. Gene targeting reveals multiple essential functions of the neuregulin signaling system during development of the neuroendocrine and nervous systems. (2002) Ann. N. Y. Acad. Sci. 971:547-53.

+ expand abstract

Vetter, D.E., Li, C., Zhao, L., Contarino, A., Liberman, M.C., Smith, G.W., Marchuk, Y., Koob, G.F., Heinemann, S.F., Vale, W., Lee, K.F. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. (2002) Nature Genetics. 31(4):363-9. DOI: 10.1038/ng914

+ expand abstract

Bale, T.L., Lee, K.F., Vale, W.W. The role of corticotropin-releasing factor receptors in stress and anxiety. (2002) Integrative and Comparative Biology. 42(3):552-5. DOI: 10.1093/icb/42.3.552

+ expand abstract

Bale, T.L., Giordano, F.J., Hickey, R.P., Huang, Y., Nath, A.K., Peterson, K.L., Vale, W.W., Lee, K.F. Corticotropin-releasing factor receptor 2 is a tonic suppressor of vascularization. (2002) Proceedings of the National Academy of Sciences of the United States of America. 99(11):7734-9. DOI: 10.1073/pnas.102187099

+ expand abstract

Crone, S.A., Zhao, Y.Y., Fan, L., Gu, Y., Minamisawa, S., Liu, Y., Peterson, K.L., Chen, J., Kahn, R., Condorelli, G., Ross, J., Chien, K.R., Lee, K.F. ErbB2 is essential in the prevention of dilated cardiomyopathy. (2002) Nature Medicine. 8(5):459-65. DOI: 10.1038/nm0502-459

+ expand abstract

Kaspar, B.K., Vissel, B., Bengoechea, T., Crone, S., Randolph-Moore, L., Muller, R., Brandon, E.P., Schaffer, D., Verma, I.M., Lee, K.F., Heinemann, S.F., Gage, F.H. Adeno-associated virus effectively mediates conditional gene modification in the brain. (2002) Proceedings of the National Academy of Sciences of the United States of America. 99(4):2320-5. DOI: 10.1073/pnas.042678699

+ expand abstract

Bale, T.L., Picetti, R., Contarino, A., Koob, G.F., Vale, W.W., Lee, K.F. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. (2002) Journal of Neuroscience. 22(1):193-9.

+ expand abstract

Lin, W., Burgess, R.W., Dominguez, B., Pfaff, S.L., Sanes, J.R., Lee, K.F. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. (2001) Nature. 410(6832):1057-64. DOI: 10.1038/35074025

+ expand abstract

Lee, S., Smith, G.W., Vale, W., Lee, K.F., Rivier, C. Mice that lack corticotropin-releasing factor (CRF) receptors type 1 show a blunted ACTH response to acute alcohol despite up-regulated constitutive hypothalamic CRF gene expression. (2001) Alcohol. Clin. Exp. Res. 25(3):427-33.

+ expand abstract

Bentley, C.A., Lee, K.F. p75 is important for axon growth and schwann cell migration during development. (2000) Journal of Neuroscience. 20(20):7706-15.

+ expand abstract

Bradbury, M.J., McBurnie, M.I., Denton, D.A., Lee, K.F., Vale, W.W. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing factor receptor 1 deficiency in mice. (2000) Endocrinology. 141(8):2715-24. DOI: 10.1210/endo.141.8.7606

+ expand abstract

Syroid, D.E., Maycox, P.J., Soilu-Hänninen, M., Petratos, S., Bucci, T., Burrola, P., Murray, S., Cheema, S., Lee, K.F., Lemke, G., Kilpatrick, T.J. Induction of postnatal schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy. (2000) Journal of Neuroscience. 20(15):5741-7.

+ expand abstract

Contarino, A., Dellu, F., Koob, G.F., Smith, G.W., Lee, K.F., Vale, W.W., Gold, L.H. Dissociation of locomotor activation and suppression of food intake induced by CRF in CRFR1-deficient mice. (2000) Endocrinology. 141(7):2698-702. DOI: 10.1210/endo.141.7.7653

+ expand abstract

Bale, T.L., Contarino, A., Smith, G.W., Chan, R., Gold, L.H., Sawchenko, P.E., Koob, G.F., Vale, W.W., Lee, K.F. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. (2000) Nature Genetics. 24(4):410-4. DOI: 10.1038/74263

+ expand abstract

Lin, W., Sanchez, H.B., Deerinck, T., Morris, J.K., Ellisman, M., Lee, K.F. Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice. (2000) Proceedings of the National Academy of Sciences of the United States of America. 97(3):1299-304.

+ expand abstract

Blume-Jensen, P., Jiang, G., Hyman, R., Lee, K.F., O’Gorman, S., Hunter, T. Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3′-kinase is essential for male fertility. (2000) Nature Genetics. 24(2):157-62. DOI: 10.1038/72814

+ expand abstract

Morris, J.K., Lin, W., Hauser, C., Marchuk, Y., Getman, D., Lee, K.F. Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. (1999) Neuron. 23(2):273-83.

+ expand abstract

Li, Q., Lu, Q., Hwang, J.Y., Büscher, D., Lee, K.F., Izpisua-Belmonte, J.C., Verma, I.M. IKK1-deficient mice exhibit abnormal development of skin and skeleton. (1999) Genes & Development. 13(10):1322-8.

+ expand abstract

Li, Q., Van Antwerp, D., Mercurio, F., Lee, K.F., Verma, I.M. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. (1999) Science. 284(5412):321-5.

+ expand abstract

Turnbull, A.V., Smith, G.W., Lee, S., Vale, W.W., Lee, K.F., Rivier, C. CRF type I receptor-deficient mice exhibit a pronounced pituitary-adrenal response to local inflammation. (1999) Endocrinology. 140(2):1013-7. DOI: 10.1210/endo.140.2.6675

+ expand abstract

Peterson, D.A., Dickinson-Anson, H.A., Leppert, J.T., Lee, K.F., Gage, F.H. Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. (1999) Journal of Comparative Neurology. 404(1):1-20.

+ expand abstract

Smith, G.W., Aubry, J.M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H., Chen, R., Marchuk, Y., Hauser, C., Bentley, C.A., Sawchenko, P.E., Koob, G.F., Vale, W., Lee, K.F. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. (1998) Neuron. 20(6):1093-102.

+ expand abstract

Wang, L., Zoppè, M., Hackeng, T.M., Griffin, J.H., Lee, K.F., Verma, I.M. A factor IX-deficient mouse model for hemophilia B gene therapy. (1997) Proceedings of the National Academy of Sciences of the United States of America. 94(21):11563-6.

+ expand abstract

Anton, E.S., Marchionni, M.A., Lee, K.F., Rakic, P. Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. (1997) Development. 124(18):3501-10.

+ expand abstract

Sarram, S., Lee, K.F., Byers, M.R. Dental innervation and CGRP in adult p75-deficient mice. (1997) Journal of Comparative Neurology. 385(2):297-308.

+ expand abstract

Adult dental tissues have unusual neurotrophin biology. Pulpal fibroblasts express nerve growth factor (NGF) and the low-affinity p75 neurotrophin receptor, their sensory nerve fibers express p75 and trk A, and pulpal sympathetic fibers lack p75. Following tooth injury, there is increased pulpal NGF, sprouting of sensory nerve endings, and increased immunoreactivity for the sensory neuropeptide calcitonin gene-related peptide (CGRP). In the present study, we have analyzed tooth structure and innervation of pulp and periodontal ligament in young (6-8 weeks, 3 months) and older (5-12 months) adult mice carrying a null mutation in the p75 gene and compared the results with those of age-matched wild-type controls. Our hypotheses were that tooth structure would be abnormal and that pulpal innervation would be greatly reduced because it consists primarily of nociceptive fibers that have been found to be severely depleted in skin of p75(-/-) mice. Tissues were fixed, X-rayed for gross dental morphology, decalcified, and analyzed for immunoreactivity for CGRP and for a general nerve marker, protein gene product 9.5. Radiographs showed worn-down molar crowns in p75-deficient mice. Light microscopy confirmed the accelerated molar wear and showed intense CGRP immunoreactivity in pulp nerve endings of mutant mice, compared with a gradual decrease in CGRP intensity in controls during normal aging. The CGRP intensity in 5-12-month-old pairs of mice was threefold greater in the mutants (P < 0.03), and in younger mice the mutant always had more CGRP than its matched control. The innervation of molar ligament in all p75-deficient mice was similar to that of controls except there was nerve sprouting near bone loss in mutants. The incisors of mutant mice did not have unusual wear and their pulpal CGRP immunoreactivity remained normal, but their periodontal ligament had fewer thin branched nerve endings at all ages. Thus, most innervation of teeth and their supporting tissues developed normally, and the only neural changes in p75(-/-) mutant mice were the reduction of incisor ligament sensory receptors and increased molar CGRP. Sensory nerves in teeth gradually lose neuropeptide intensity during aging, but that did not happen in the mutant mice, suggesting that the accelerated molar wear stimulated persistent high levels of CGRP.

Lee, S., Rivier, C. Effect of repeated activin-A treatment on the activity of the hypothalamic-pituitary-gonadal axis of the adult male rat. (1997) Biol. Reprod. 56(4):969-75.

+ expand abstract

Syroid, D.E., Maycox, P.R., Burrola, P.G., Liu, N., Wen, D., Lee, K.F., Lemke, G., Kilpatrick, T.J. Cell death in the Schwann cell lineage and its regulation by neuregulin. (1996) Proceedings of the National Academy of Sciences of the United States of America. 93(17):9229-34.

+ expand abstract

ElShamy, W.M., Linnarsson, S., Lee, K.F., Jaenisch, R., Ernfors, P. Prenatal and postnatal requirements of NT-3 for sympathetic neuroblast survival and innervation of specific targets. (1996) Development. 122(2):491-500.

+ expand abstract

Lee, K.F., Simon, H., Chen, H., Bates, B., Hung, M.C., Hauser, C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. (1995) Nature. 378(6555):394-8. DOI: 10.1038/378394a0

+ expand abstract

Ernfors, P., Kucera, J., Lee, K.F., Loring, J., Jaenisch, R. Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. (1995) International Journal of Developmental Biology. 39(5):799-807.

+ expand abstract

Curtis, R., Adryan, K.M., Stark, J.L., Park, J.S., Compton, D.L., Weskamp, G., Huber, L.J., Chao, M.V., Jaenisch, R., Lee, K.F. Differential role of the low affinity neurotrophin receptor (p75) in retrograde axonal transport of the neurotrophins. (1995) Neuron. 14(6):1201-11.

+ expand abstract

Ernfors, P., Lee, K.F., Kucera, J., Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. (1994) Cell. 77(4):503-12.

+ expand abstract

Lee, K.F., Davies, A.M., Jaenisch, R. p75-deficient embryonic dorsal root sensory and neonatal sympathetic neurons display a decreased sensitivity to NGF. (1994) Development. 120(4):1027-33.

+ expand abstract

Lee, K.F., Bachman, K., Landis, S., Jaenisch, R. Dependence on p75 for innervation of some sympathetic targets. (1994) Science. 263(5152):1447-9.

+ expand abstract

Ernfors, P., Lee, K.F., Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. (1994) Nature. 368(6467):147-50. DOI: 10.1038/368147a0

+ expand abstract

Vassalli, A., Matzuk, M.M., Gardner, H.A., Lee, K.F., Jaenisch, R. Activin/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction. (1994) Genes & Development. 8(4):414-27.

+ expand abstract

Ernfors, P., Lee, K.F., Jaenisch, R. Target derived and putative local actions of neurotrophins in the peripheral nervous system. (1994) Progress in Brain Research. 103:43-54.

Davies, A.M., Lee, K.F., Jaenisch, R. p75-deficient trigeminal sensory neurons have an altered response to NGF but not to other neurotrophins. (1993) Neuron. 11(4):565-74.

+ expand abstract

Lee, K.F., Li, E., Huber, L.J., Landis, S.C., Sharpe, A.H., Chao, M.V., Jaenisch, R. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. (1992) Cell. 69(5):737-49.

+ expand abstract

Rosen, J.M., Bayna, E., Lee, K.F. Analysis of milk protein gene expression in transgenic mice. (1989) Molecular Biology & Medicine. 6(6):501-9.

Rosen, J.M., Poyet, P., Goodman, H., Lee, K.F. Mechanisms by which prolactin and glucocorticoids regulate casein gene expression. (1989) Biochemical Society Symposium. 55:115-23.

Lee, K.F., Atiee, S.H., Henning, S.J., Rosen, J.M. Relative contribution of promoter and intragenic sequences in the hormonal regulation of rat beta-casein transgenes. (1989) Molecular Endocrinology. 3(3):447-53. DOI: 10.1210/mend-3-3-447

+ expand abstract

Lee, K.F., Atiee, S.H., Rosen, J.M. Differential regulation of rat beta-casein-chloramphenicol acetyltransferase fusion gene expression in transgenic mice. (1989) Molecular and Cellular Biology. 9(2):560-5.

+ expand abstract

Lee, K.F., DeMayo, F.J., Atiee, S.H., Rosen, J.M. Tissue-specific expression of the rat beta-casein gene in transgenic mice. (1988) Nucleic Acids Research. 16(3):1027-41.

+ expand abstract