Professor of Pediatric Neurology and
Adjunct Associate Professor of Neurobiology and of Neurology
Chief, Division of Pediatric Neurology
Director, Primary Children's Center for Pediatric Personalized Medicine
B.A. Harvard University
M.D./Ph.D. University of California, San Diego
Josh Bonkowsky's Lab Page
Josh Bonkowsky's PubMed Literature Search
Molecular Biology Program
Function of human disease genes in CNS development
Axon pathfinding and development of CNS connectivity; function of human disease genes in CNS development
Our research is centered on studying the development of CNS connectivity and neurodevelopmental
disorders. Neurodevelopmental disorders are very common, but poorly understood in
terms of their pathophysiology and effects on CNS development.
1. Developmental functions of human disease genes.
- We are studying human leukodystrophies. Inherited leukodystrophies are diseases of the myelin, including abnormal myelin development, hypomyelination, or degeneration of myelin. The incidence of leukodystrophies is almost 1 in 7500 live births. Typical disease presentation occurs in the first three years of life with a 34% risk of death by age 8 years (Bonkowsky et al., 2010).
- Vanishing white matter disease (VWMD) is a frequent cause of leukodystrophies with no known cure. VWMD is an autosomal recessive leukodystrophy caused by mutations in the eukaryotic initiation factor 2B (eif2B) gene family.
- We are developing zebrafish models of VWMD, as well as of other common leukodystrophies including ALD, MLD, and PMD.
2. Effects of hypoxia on CNS Development.
- Hypoxic injury to the developing human brain causes life-long intellectual and behavioral deficits. These serious outcomes include autism spectrum disorders, cerebral palsy, depression, epilepsy, and intellectual disabilities. Currently there are no treatments to protect against the effects of prematurity and chronic hypoxic injury to the central nervous system (CNS). The ultimate goal of our research is to understand the fundamental molecular and neurobiological mechanisms by which hypoxia disrupts connectivity.
- We use a combination of novel transgenic lines and innovative chemical and imaging approaches. Elucidation of these mechanisms offers the potential for designing effective and targeted therapeutic approaches.
- We are collaborating closely with our clinical colleagues to understand the roles and contributions of genetic changes to pediatric disease, particularly in patients with leukodystrophies and epilepsy.
- We have several gene therapy projects in process; as well as the development of novel therapeutic approaches to pediatric disease.
- Using large national databases, we are studying hidden patterns of disease and new potentials to improve pediatric health.
Bonkowsky JL, Wilkes J, Bardsley T, Urbik VM*, Stoddard G. Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients. JAMA Netw Open. 2018 Nov 2;1(7):e185031.
Bonkowsky JL, Son JH. Hypoxia and connectivity in the developing vertebrate nervous system. Dis Model Mech. 2018 Dec 12;11(12).
Bonkowsky JL, Wilkes J, Shyr DC. Scope and Burden of Non-Standard of Care Hematopoietic Stem Cell Transplantation in Pediatric Leukodystrophy Patients. J Child Neurol. 2018 Dec;33(14):882-887.
Bakian AV, Bilder DA, Korgenski EK, Bonkowsky JL. Autism Spectrum Disorder and Neonatal Serum Magnesium Levels in Preterm Infants. Child Neurol Open. 2018 Sep 18;5:2329048X18800566.
Ostrander BEP, Butterfield RJ, Pedersen BS, Farrell AJ, Layer RM, Ward A, Miller C, DiSera T, Filloux FM, Candee MS, Newcomb T, Bonkowsky JL^, Marth GT^, Quinlan AR^. Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy. NPJ Genom Med. 2018 Aug 13;3:22. ^ co-senior authors.
- Gao J, Stevenson TJ, Douglass AD, Barrios JP, Bonkowsky JL. The Midline Axon Crossing Decision Is Regulated through an Activity-Dependent Mechanism by the NMDA Receptor. ENeuro. 2018. 17;5(2).
- Lambert CJ, Freshner BC, Chung A, Stevenson TJ, Bowles DM, Samuel R, Gale BK, Bonkowsky JL. An automated system for rapid cellular extraction from live zebrafish embryos and larvae: Development and application to genotyping. PLoS One. 2018. 15;13(3):e0193180.
- Strachan LR, Stevenson TJ, Freshner B, Keefe MD, Miranda Bowles D, Bonkowsky JL. A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement fro abcdl in oligodenrocyte patterning and myelination. Hum Mol Genet. 2017. 15;26(18):3600-3614.
- Keefe MD, Bonkowsky JL. Transvection Arising from Transgene Interactions in Zebrafish. Zebrafish. 2017. 14(1):8-9.
- Chen YC, Semenova S, Rozov S, Sundvik M, Bonkowsky JL, Panula P. A Novel Developmental Role for Dopminergic Signaling to Secify Hypothalamic Neurotransmitter Identity. J Biol Chem. 2016. 14;291(42):21880-21892.
- Milash B, Gao J, Stevenson TJ, Son JH, Dahl T, Bonkowsky JL. Temporal Dysynchrony in brain connectivity gene expression following hypoxia. BMC Genomics. 2016. 17(1):334.
- Son JH, Keefe MD, Stevenson TJ, Barrios JP, Anjewierden S, Newton JB, Douglass AD, Bonkowsky JL. Transgenic FingRs for Live Mapping of Synaptic Dynamics in Genetically-Defined Neurons. Scientific Reports (Nature). 2016. 6:18734.
- Xing L, Son JH, Stevenson TJ, Lillesaar C, Bally-Cuif L, Dahl T, Bonkowsky JL. A Serotonin Circuit Acts as an Environmental Sensor to Mediate Midline Axon Crossing through EphrinB2. Journal of Neuroscience. 2015. 35(44):14794-808.
- Samuel R, Stephenson R, Roy P, Pryor R, Zhou L, Bonkowsky JL*, Gale BK*. Microfluidic-aided genotyping of zebrafish in the first 48 h with 100% viability. Biomedical Microdevices. 2015. 17(2):43.
- Anderson HM, Wilkes J, Korgenski EK, Pulsipher MA, Blaschke AJ, Hersh AL, Srivastava R, Bonkowsky JL. Preventable Infections in Children with Leukodystrophy. Annals of Clinical and Translational Neurology. 2014. 1(5):370-374.
- Purnell SM, Bleyl SB, Bonkowsky JL. Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy. Pediatric Neurology. 2014. 50(6):608-11.
- Xing, L., Quist, T., Stevenson, T., Dahlem, T., Bonkowsky JL. Rapid and Efficient Zebrafish Genotyping Using PCR with High-resolution Melt Analysis. Journal of Visualized Experiments. 2014 Feb 5;(84):e51138.
- Schweitzer J, Löhr H, Bonkowsky JL, Hübscher K, Driever W. Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism. Development. 2013. 140(1):93-106.
- Xing L, Hoshijima K, Grunwald DJ, Fujimoto E, Quist TS, Sneddon J, Chien CB, Stevenson TJ, Bonkowsky JL. Zebrafish foxP2 zinc finger nuclease mutant has normal axon pathfinding. PLoS One. 2012. 7(8):e43968.
- Lambert AM, Bonkowsky JL, Masino MA. The dopaminergic diencephalospinal tract mediates a developmental switch in the locomotor pattern of larval zebrafish. Journal of Neuroscience. 2012. 32:13488-13500
- Stevenson TJ, Trinh T, Kogelschatz C, Fujimoto E, Lush ME, Piotrowski T, Brimley CJ, Bonkowsky JL. Hypoxia disruption of vertebrate CNS pathfinding through EphrinB2 is rescued by magnesium. PLoS Genetics. 2012. 8(4):e1002638.
- Lakhina V, Maraccio C, Shao X, Lush M, Jain R, Fujimoto E, Bonkowsky JL, Granato M, Raper J. Netrin/DCC signaling guides olfactory sensory axons to their correct location in the olfactory bulb. Journal of Neuroscience. 2012. 32(13):4440-56.
- Gutnick A, Blechman J, Kaslin J, Affolter M, Bonkowky JL, Levkowitz G. The hypothalamic neuropeptide oxytocin is required for formation of the neuro-vascular interface of the pituitary. Developmental Cell. 2011. 18:642-54.
- Fujimoto E, Gaynes B, Brimley CJ, Chien CB, Bonkowsky JL. Gal80 Intersectional Regulation of Cell-Type Specific Expression in Vertebrates. Developmental Dynamics. 2011. 240(10):2324-34.
- Fujimoto E, Stevenson TJ, Chien CB, Bonkowsky JL. Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification. Developmental Biology. 2011. 352(2):393-404.
- Kastenhuber E, Kern U, Bonkowsky JL, Chien CB, Driever W, Schweitzer J. Netrin-DCC, Robo-Slit and HSPGs coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons. Journal of Neuroscience. 2009. 29:8914-26.
- Bonkowsky JL, Wang X, Fujimoto E, Lee EJ, Chien CB, Dorsky RI. Domain-specific regulation of foxP2 CNS expression by lef1. BMC Developmental Biology. 2008. 8:103.
- Bonkowsky JL, Chien CB. Isolation and cloning of zebrafish foxP2. Developmental Dynamics. 2005. 234:740-6.
- Bonkowsky JL, Bohnsack, JF, Pennington MJ, Viskochil D, Thompson JA. Leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia (LACH) in two brothers: a novel syndrome? American Journal of Medical Genetics. 2004. 128:52-56.
- Bonkowsky JL, Johnson J, Carey J, Smith AD, Swoboda K. An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. Pediatrics. 2003. 112:e237-241.
- Bonkowsky JL*, Yoshikawa S*, O’Keefe DD, Scully AL, Thomas JB. Axon routing across the midline controlled by the Drosophila Derailed receptor. Nature. 1999. 402: 540-4.
- Yoshikawa S*, Bonkowsky JL*, Kokel M, Shyn S, Thomas, JB. The Derailed guidance receptor does not require kinase activity in vivo. Journal of Neuroscience. 2001. 21: RC119.