Our laboratory seeks to define regulatory interactions in the developing nervous system and to understand how perturbations of development result in disease. In particular, we study the role of neuronal growth factors in the functional maturation of neural systems using genetically engineered mice and tissue culture model systems.

A major focus of the laboratory is to elucidate the molecular pathogenesis of Rett Syndrome (RTT), a devastating developmental disorder characterized by cognitive, motor and autonomic dysfunction, and to develop potential treatments. In particular, we are studying how loss of MeCP2, the gene mutated in RTT, disrupts expression and secretion of Brain Derived Neurotrophic Factor (BDNF), a protein that is critical for development, function and plasticity of many neurons in the brain and peripheral nervous system. We have found that the normal interplay between neuronal activity, and expression and secretion of BDNF, is dysregulated in MeCP2 null mice. In particular, loss of MeCP2 results in a progressive decline in the ability of neurons to synthesize and secrete normal levels of BDNF after birth. Some of the earliest changes occur in brain structures that are critical for the control of breathing and other homeostatic functions that are adversely affected in Rett patients. In fact, MeCP2 null mice exhibit severe respiratory defects, as in RTT patients. Current efforts are focused on defining underlying mechanisms and on developing BDNF-based therapies for this disease.

1. Taneja, P., Ogier, M., Brooks-Harris, G., Katz, D.M. and S. B. Nelson (2009)
   Pathophysiology of locus coeruleus neurons in a mouse model of Rett Syndrome J. Neurosci. 29:12187-12195.
   
2. Ladas, T., Chan, S-A., Ogier, M., Smith, C. and D. M. Katz (2009)
   Enhanced dense core granule function and adrenal hypersecretion in a mouse model of Rett Syndrome Eur. J. Neurosci. 30(2):602-10.
   
3. Katz, D.M., Dutschmann, M., Ramirez, N. and G. Hilaire (2009)
   Breathing disorders in Rett Syndrome: Progressive neurochemical dysfunction in the respiratory network after birth Resp. Physiol. and Neurobiol. 168:101-8.
   
4. Bouvier, J., Autran, S., Dehorter, N., Katz, D.M., Champagnat, J., Fortin, G. and Thoby-Brisson, M. (2008)
   The embryonic pre-Bötzinger complex is a target of Brain-Derived Neurotrophic Factor J Neurosci. 28:510-520.
   
5. Ogier, M., Wang H., Hong, E., Wang, Q., Greenberg, M.E. and D. M. Katz. (2007)
   Brain Derived Neurotrophic Factor and respiratory function improve after ampakine treatment in a mouse model of Rett Syndrome. J Neurosci. 27:10912-7.
   
6. Wang, H., Chan, S., Ogier, M., Hellard, D., Wang, Q., Smith, C. and D.M. Katz. (2006)
   Dysregulation of BDNF expression and neurosecretion in MeCP2 null mice. J Neurosci. 26:10911-10915.
   
7. Wang, H., Yuan, G., Ward, N., Boswell, M. and D.M. Katz. (2006)
   Secretion of brain derived neurotrophic factor from brain microvascular endothelial cells. Eur J Neurosci. 2006; 96(6):1665-70.
   
8. Wang H, Yuan G, Prabhakar NR, Boswell M, Katz DM. (2006)
   Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling. J Neurochem. 2006 Feb; 96(3):694-705.
   
9. Katz DM. (2005)
   Regulation of respiratory neuron development by neurotrophic and transcriptional signaling mechanisms. Respir Physiol Neurobiol. 2005 Nov 15; 149(1-3):99-109.
   
10. Guo H, Hellard DT, Huang L, Katz DM. (2005)
    Development of pontine noradrenergic A5 neurons requires brain-derived neurotrophic factor. Eur J Neurosci. 2005 Apr; 21(7):2019-2023.
    
11. Huang L, Guo H, Hellard DT, Katz DM. (2005)
    Glial cell line-derived neurotrophic factor (GDNF) is required for differentiation of pontine noradrenergic neurons and patterning of central respiratory output. Neuroscience. 2005; 130(1):95-105.
    
12. Hellard D, Brosenitsch T, Fritzsch B, Katz DM. (2004)
    Cranial sensory neuron development in the absence of brain-derived neurotrophic factor in BDNF/Bax double null mice. Dev Biol. 2004 Nov 1; 275(1):34-43.
    
13. Thoby-Brisson M, Cauli B, Champagnat J, Fortin G, Katz DM. (2003)
    Expression of functional tyrosine kinase B receptors by rhythmically active respiratory neurons in the pre-Botzinger complex of neonatal mice. J Neurosci. 2003 Aug 20; 23(20):7685-7689.
    
14. Balkowiec A, Katz DM. (2002)
    Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci. 2002 Dec 1; 22(23):10399-10407.
    
15. Brosenitsch TA, Katz DM. (2002)
    Expression of Phox2 transcription factors and induction of the dopaminergic phenotype in primary sensory neurons. Mol Cell Neurosci. 2002 Jul; 20(3):447-457.
    
16. Brosenitsch TA, Katz DM. (2001)
    Physiological patterns of electrical stimulation can induce neuronal gene expression by activating N-type calcium channels. J Neurosci. 2001 Apr 15; 21(8):2571-2579.
    
17. Erickson JT, Brosenitsch TA, Katz DM. (2001)
    Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor are required simultaneously for survival of dopaminergic primary sensory neurons in vivo. J Neurosci. 2001 Jan 15; 21(2):581-589.
    
18. Balkowiec A, Katz DM. (2000)
    Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci. 2000 Oct 1; 20(19):7417-7423.
    
19. Balkowiec A, Kunze DL, Katz DM. (2000)
    Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons. J Neurosci. 2000 Mar 1; 20(5):1904-1911.
    
20. Brady R, Zaidi SI, Mayer C, Katz DM. (1999)
    BDNF is a target-derived survival factor for arterial baroreceptor and chemoafferent primary sensory neurons. J Neurosci. 1999 Mar 15; 19(6):2131-2142.
    
21. Balkowiec A, Katz DM. (1998)
    Brain-derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice. J Physiol. 1998 Jul 15; 510 ( Pt 2):527-533.
    
22. Katz DM, Balkowiec A. (1997)
    New insights into the ontogeny of breathing from genetically engineered mice. Curr Opin Pulm Med. 1997 Nov; 3(6):433-439.
    
23. Erickson JT, Conover JC, Borday V, Champagnat J, Barbacid M, Yancopoulos G, Katz DM. (1996)
    Mice lacking brain-derived neurotrophic factor exhibit visceral sensory neuron losses distinct from mice lacking NT4 and display a severe developmental deficit in control of breathing. J Neurosci. 1996 Sep 1; 16(17):5361-5371.
    
24. Conover JC, Erickson JT, Katz DM, Bianchi LM, Poueymirou WT, McClain J, Pan L, Helgren M, Ip NY, Boland P, et al.. (1995)
    Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature. 1995 May 18; 375(6528):235-238.