ORAL PRESENTATIONS - SESSION 1

Transgenic approaches to the study of respiratory function

DM Katz

Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4975, USA

corresponding author email

Neural Control of Breathing
Rotorua, New Zealand, 1-4 September 2001

Respiratory Research 2001, 2(Suppl 1):1.6doi:10.1186/rr93

Received:	2 August 2001
Published:	17 August 2001

© 2001 BioMed Central Ltd

ORAL PRESENTATIONS - SESSION 1

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 [5]. 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.

Acknowledgement

Supported by USPHS grants (NHLBI) to DMK.

References

1. 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. PubMed Abstract | Publisher Full Text

2. 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. PubMed Abstract

3. 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. PubMed Abstract | Publisher Full Text

4. 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. PubMed Abstract | Publisher Full Text

5. 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. PubMed Abstract | Publisher Full Text

6. 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. PubMed Abstract | Publisher Full Text

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