Transgenic approaches to the study of respiratory function
Respiratory Research volume 2, Article number: 1.6 (2001)
Genetically engineered mice have proven an invaluable tool for establishing linkages between individual genes and the generation of complex behaviors, including respiration. This presentation will focus on the use of mice carrying targeted gene deletions (gene knockouts) to elucidate the role of neuronal growth factors in the development of the neural respiratory controller and breathing behavior. In particular, I will focus on the role of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in development of peripheral chemoafferent neurons and central respiratory output. Initial studies in my laboratory demonstrated that mice that are homozygous for a null mutation at the bdnf locus exhibit a severe developmental deficit in control of breathing, characterized by depressed and irregular ventilation and central respiratory output and a lack of hypoxic ventilatory drive [1,2]. These deficits are due at least in part to loss of peripheral chemoafferent neurons that require BDNF for survival during fetal development [1,3,4]. Surprisingly, null mutations in the gdnf gene result in a similar phenotype, despite the fact that BDNF and GDNF are structurally unrelated and signal through wholly different classes of receptors. However, we recently found that BDNF and GDNF are both required for survival of the same population of chemoafferent neurons and that null mutations in either gene results in chemoafferent cell loss . This dual requirement for BDNF and GDNF appears to be related to the fact that both molecules are expressed in the fetal carotid body and act as target-derived survival factors for chemoafferent neurons [5,6]. Loss of chemoafferent input at fetal stages is particularly deleterious for maturation of ventilatory function, as chemoafferent drive is required for stabilization of central respiratory output after birth. Potential implications of these findings for human developmental disorders of breathing will be discussed.
Erickson JT, Conover JC, Borday V, Champagnat J, Barbacid M, Yancopoulos GD, Katz DM: 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, 16: 5361-5371.
Balkowiec A, Katz DM: Brain-derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice. J Physiol. 1998, 510: 527-533. 10.1111/j.1469-7793.1998.527bk.x.
Hertzberg TH, Erickson JT, Fan G, Finley JCW, Katz DM: BDNF supports mammalian chemoafferent neurons in vitro and following peripheral target removal in vivo. Dev Biol. 1994, 166: 801-811. 10.1006/dbio.1994.1358.
Conover JC, Katz DM, Erickson JT, Bianchi LM, Poueymirou WT, McClain J, Pan L, Helgren M, Ip NY, Boland P, et al: Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature. 1995, 375: 235-238. 10.1038/375235a0.
Brady R, Zaidi IAS, Mayer C, Katz DM: BDNF is a target-derived survival factor for arterial baroreceptor and chemoafferent primary sensory neurons. J Neurosci. 1999, 19: 2131-2142.
Erickson JT, Brosenitsch T, Katz DM: 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, 21: 581-589.
Supported by USPHS grants (NHLBI) to DMK.