Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality

Abstract

Heterozygous mutation or deletion of the ß subunit of platelet-activating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration. To further understand the function of PAFAH1B1, we produced three different mutant alleles in mouse Pafah1b1. Homozygous null mice die early in embryogenesis soon after implantation. Mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects. Our results demonstrate an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration.

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Figure 1: Generation of Pafah1b1 mutant mice.
Figure 2: Early embryonic lethality of Pafah1b1-neo homozygous mice.
Figure 3: Morphological abnormalities in brains of Pafah1b1 heterozygous mutant mice.
Figure 4: Morphological abnormalities in brains of Pafah1b1 mutants.
Figure 5: In vivo analysis of neuronal migration.
Figure 6: In vitro analysis of neuronal migration.

References

  1. 1

    Rakic, P. Specification of cerebral cortical areas. Science 241, 170–6 (1988).

    CAS  Article  Google Scholar 

  2. 2

    Reid, C.B. & Walsh, C.A. in Progress in Brain Research (eds Mize, R.R. & Erzurumlu, R.S.) 17–30 (Elsevier Science, New York, 1996).

    Google Scholar 

  3. 3

    Rakic, P. Neuronal migration and contact guidance in the primate telencephalon. Postgrad. Med. J. 54, 25–40 ( 1978).

    PubMed  Google Scholar 

  4. 4

    McConnell, S.K. Development and decision-making in the mammalian cerebral cortex. Brain Res. Rev. 13, 1–23 ( 1988).

    Article  Google Scholar 

  5. 5

    Rakic, P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 61–84 ( 1972).

    CAS  Article  Google Scholar 

  6. 6

    Hatten, M.E. Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the mammalian mammalian brain. Trends Neurosci. 13, 179–184 ( 1990).

    CAS  Article  Google Scholar 

  7. 7

    Hatten, M.E. & Heintz, N. Mechanisms of neural patterning and specification in the developing cerebellum. Annu. Rev. Neurosci. 18, 385–408 ( 1995).

    CAS  Article  Google Scholar 

  8. 8

    O'Rourke, N.A. Neuronal chain gangs: homotypic contacts support migration into the olfactory bulb . Neuron 16, 1061–1064 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Caviness, V.S. Jr., & Rakic, P. Mechanism of cortical development: a review from mutations in mice. Annu. Rev. Neurosci. 1, 297–326 ( 1978).

    Article  Google Scholar 

  10. 10

    Goffinet, A. Events governing organization of postmigratory neurons: studies on brain development in normal and reeler mice. Brain Res. Rev. 7, 261– 296 (1984).

    Article  Google Scholar 

  11. 11

    Rakic, P. & Caviness, V.S., Jr., Cortical development: view from neurological mutants two decades later. Neuron 14, 1101–1104 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Ware, M.L. et al. Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse. Neuron 19, 239– 249 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Sheldon, M. et al. Scramber and yotari disrupt the disabled gene and produce a reeler-like phenotype. Nature 389, 730–733 (1997).

    CAS  Google Scholar 

  14. 14

    Howell, B.W., Hawkes, R., Soriano, P. & Cooper, J.A. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, 733–737 ( 1997).

    CAS  Article  Google Scholar 

  15. 15

    Oshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).

    Article  Google Scholar 

  16. 16

    Chae, T. et al. Mice lacking p35, a neuronal-specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).

    CAS  Article  Google Scholar 

  17. 17

    D'Arcangelo, G. et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719– 23 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Hirotsune, S. et al. The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nature Genet. 10, 77 –83 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Tsai, L.H., Delalle, I., Caviness, V.S., Jr., Chae, T. & Harlow, E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419–23 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Tsai, L.H., Takahashi, T., Caviness, V.S. Jr., & Harlow, E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 119, 1029 –1040 (1993).

    CAS  PubMed  Google Scholar 

  21. 21

    Barkovich, A.J. et al. A classification scheme for malformations of cortical development. Neuropediatrics 27, 59–63 (1996).

    CAS  Article  Google Scholar 

  22. 22

    Dobyns, W.B., Reiner, O., Carrozzo, R. & Ledbetter, D.H. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. J.A.M.A. 270, 2838–2842 (1993).

    CAS  Article  Google Scholar 

  23. 23

    Reiner, O. et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 364, 717– 721 (1993).

    CAS  Article  Google Scholar 

  24. 24

    Lo Nigro, C. et al. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum. Mol. Genet. 6, 157– 164 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Hattori, M., Adachi, H., Tsujimoto, M., Arai, H. & Inoue, K. Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase. Nature 370, 216– 218 (1994).

    CAS  Article  Google Scholar 

  26. 26

    Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl Acad. Sci. USA 93, 5860 –5865 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Deng, C.X. et al. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev. 8, 3045– 3057 (1994).

    CAS  Article  Google Scholar 

  28. 28

    Caviness, V.S., Jr., Neocortical histogenesis in normal and reeler mice: a developmental study based upon [3H]thymidine autoradiography. Dev. Brain Res. 4, 293–302 ( 1982).

    Article  Google Scholar 

  29. 29

    Asou, H., Miura, M., Kobayashi, M., Uyemura, K. & Itoh, K. Cell adhesion molecule L1 guides cell migration in primary reaggregation cultures of mouse cerebellar cells. Neurosci. Lett. 144, 221–224 ( 1992).

    CAS  Article  Google Scholar 

  30. 30

    Bix, G.J. & Clark, G.D. Platelet-activating factor receptor stimulation disrupts neuronal migration in vitro. J. Neurosci. 18, 307–318 ( 1998).

    CAS  Article  Google Scholar 

  31. 31

    Reiner, O. et al. Lissencephaly gene (LIS1) expression in the CNS suggests a role in neuronal migration. J. Neurosci. 15, 3730 –3738 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Albrecht, U. et al. Platelet-activating factor acetylhydrolase expression and activity suggest a link between neuronal migration and platelet-activating factor. Dev. Biol. 180, 579–593 (1996).

    CAS  Article  Google Scholar 

  33. 33

    Clark, G.D., McNeil, R.S., Bix, G.J. & Swann, J.W. Platelet-activating factor produces neuronal growth cone collapse. Neuroreport 6, 2569–2575 (1995).

    CAS  Article  Google Scholar 

  34. 34

    Sapir, T., Elbaum, M. & Reiner, O. Reduction of microtubule catastrophe events by LIS1, a platelet activating factor acetylhydrolase subunit. EMBO J. 16, 6977–6984 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Xiang, X., Osmani, A.H., Osmani, S.A., Xin, M. & Morris, N.R. NudF, a nuclear migration gene in Aspergillus nidulans, is similar to the human LIS-1 gene required for neuronal migration . Mol. Biol. Cell 6, 297– 310 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Willins, D.A., Xiang, X. & Morris, N.R. An alpha tubulin mutation suppresses nuclear migration mutations in Aspergillus nidulans. Genetics 141, 1287– 1298 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Nagata, I. & Terashima, T. Migration behavior of granule cells on laminin in cerebellar microexplant cultures from early postnatal reeler mutant mice. Int. J. Dev. Neurosci. 12, 387–395 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Hirotsune, S. et al. Genomic organization of the murine Miller-Dieker/lissencephaly region: conservation of linkage with the human region. Genome Res. 7, 625–634 (1997).

    CAS  Article  Google Scholar 

  39. 39

    Tybulewicz, V.L., Crawford, C.E., Jackson, P.K., Bronson, R.T. & Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 ( 1991).

    CAS  Article  Google Scholar 

  40. 40

    Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth . Cell 84, 911–921 (1996).

    CAS  Article  Google Scholar 

  41. 41

    Luna, L.G. Histopathological methods and color atlas of special stains and tissue. (American Histolabs, Inc. Publications Division, Gaithersburg,1992).

    Google Scholar 

  42. 42

    Dover, R. & Patel, K. Improved methodology for detecting bromodeoxyuridine in cultured cells and tissue sections by immunocytohistochemistry . Histochemistry 102, 383– 387 (1994).

    CAS  Article  Google Scholar 

  43. 43

    Garrett, W.M. & Guthrie, H.D. Detection of bromodeoxyuridine in paraffin-embedded tissue sections using microwave antigen retrieval is dependent upon the mode of tissue fixation. Biochimica 1, 17–20 (1998).

    Google Scholar 

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Correspondence to Anthony Wynshaw-Boris.

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Hirotsune, S., Fleck, M., Gambello, M. et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat Genet 19, 333–339 (1998). https://doi.org/10.1038/1221

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