Axon guidance molecules determine the pattern of neuronal circuits. Accuracy of the process is ensured by unknown mechanisms that correct early guidance errors. Since the time frame of error correction in Sema3A null mice partly overlaps with the period of naturally occurring cell death in dorsal root ganglia (DRG) development, we tested the hypothesis that apoptosis of misguided neurons enables error correction. We crossed BAX null mice, in which DRG apoptosis is blocked, with Sema3A null mice to induce errors. Analyses of these double-null mouse embryos showed that the elimination of abnormal projections is not blocked in the absence of BAX. Surprisingly however, there are fewer surviving neurons in Sema3A null or Sema3A/BAX double-null newborn mice than in wild-type mice. These results suggest that guidance errors are corrected by a BAX-independent cell death mechanism. Thus, aberrant axonal guidance may lead to reductions in neuronal numbers to suboptimal levels, perhaps increasing the likelihood of neuropathological consequences later in life.
References
[1]
Tosney KW, Landmesser LT (1985) Specificity of early motoneuron growth cone outgrowth in the chick embryo. J Neurosci 5: 2336–2344.
[2]
Kolodkin AL, Tessier-Lavigne M (2011) Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb Perspect Biol 3.
[3]
Fujisawa H (2004) Discovery of semaphorin receptors, neuropilin and plexin, and their functions in neural development. J Neurobiol 59: 24–33.
[4]
White FA, Behar O (2000) The development and subsequent elimination of aberrant peripheral axon projections in Semaphorin3A null mutant mice. Dev Biol 225: 79–86.
[5]
Masuda T, Watanabe K, Sakuma C, Ikenaka K, Ono K, et al. (2008) Netrin-1 acts as a repulsive guidance cue for sensory axonal projections toward the spinal cord. J Neurosci 28: 10380–10385.
[6]
Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14: 453–501.
[7]
White FA, Keller-Peck CR, Knudson CM, Korsmeyer SJ, Snider WD (1998) Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J Neurosci 18: 1428–1439.
[8]
Patel TD, Jackman A, Rice FL, Kucera J, Snider WD (2000) Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 25: 345–357.
[9]
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 275: 34–43.
[10]
Kuruvilla R, Zweifel LS, Glebova NO, Lonze BE, Valdez G, et al. (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118: 243–255.
[11]
Wickramasinghe SR, Alvania RS, Ramanan N, Wood JN, Mandai K, et al. (2008) Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58: 532–545.
[12]
Genc B, Ozdinler PH, Mendoza AE, Erzurumlu RS (2004) A chemoattractant role for NT-3 in proprioceptive axon guidance. PLoS Biol 2: e403.
[13]
Ben-Zvi A, Manor O, Schachner M, Yaron A, Tessier-Lavigne M, et al. (2008) The Semaphorin receptor PlexinA3 mediates neuronal apoptosis during dorsal root ganglia development. J Neurosci 28: 12427–12432.
[14]
West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22: 51–61.
[15]
Lerman O, Ben-Zvi A, Yagil Z, Behar O (2007) Semaphorin3A accelerates neuronal polarity in vitro and in its absence the orientation of DRG neuronal polarity in vivo is distorted. Mol Cell Neurosci 36: 222–234.
[16]
Haupt C, Kloos K, Faus-Kessler T, Huber AB (2010) Semaphorin 3A-Neuropilin-1 signaling regulates peripheral axon fasciculation and pathfinding but not developmental cell death patterns. Eur J Neurosci 31: 1164–1172.
[17]
Sun W, Gould TW, Vinsant S, Prevette D, Oppenheim RW (2003) Neuromuscular development after the prevention of naturally occurring neuronal death by Bax deletion. J Neurosci 23: 7298–7310.
[18]
Kawakami A, Kitsukawa T, Takagi S, Fujisawa H (1996) Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J Neurobiol 29: 1–17.
[19]
Ben-Zvi A, Yagil Z, Hagalili Y, Klein H, Lerman O, et al. (2006) Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons. J Neurochem 96: 585–597.
[20]
Gagliardini V, Fankhauser C (1999) Semaphorin III can induce death in sensory neurons. Mol Cell Neurosci 14: 301–316.
[21]
Yuan J, Lipinski M, Degterev A (2003) Diversity in the mechanisms of neuronal cell death. Neuron 40: 401–413.
[22]
Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16: 966–975.
[23]
Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24: 677–736.
[24]
Wang H, Tessier-Lavigne M (1999) En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS. Nature 401: 765–769.
[25]
Gao PP, Sun CH, Zhou XF, DiCicco-Bloom E, Zhou R (2000) Ephrins stimulate or inhibit neurite outgrowth and survival as a function of neuronal cell type. J Neurosci Res 60: 427–436.
[26]
Sharma A, Verhaagen J, Harvey AR (2012) Receptor complexes for each of the Class 3 Semaphorins. Front Cell Neurosci 6: 28.
[27]
Tomizawa Y, Sekido Y, Kondo M, Gao B, Yokota J, et al. (2001) Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A 98: 13954–13959.
[28]
Bai G, Chivatakarn O, Bonanomi D, Lettieri K, Franco L, et al. (2011) Presenilin-dependent receptor processing is required for axon guidance. Cell 144: 106–118.
