AP2γ regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex

  • A Corrigendum to this article was published on 01 May 2010

Abstract

An important feature of the cerebral cortex is its layered organization, which is modulated in an area-specific manner. We found that the transcription factor AP2γ regulates laminar fate in a region-specific manner. Deletion of AP2γ (also known as Tcfap2c) during development resulted in a specific reduction of upper layer neurons in the occipital cortex, leading to impaired function and enhanced plasticity of the adult visual cortex. AP2γ functions in apical progenitors, and its absence resulted in mis-specification of basal progenitors in the occipital cortex at the time at which upper layer neurons were generated. AP2γ directly regulated the basal progenitor fate determinants Math3 (also known as Neurod4) and Tbr2, and its overexpression promoted the generation of layer II/III neurons in a time- and region-specific manner. Thus, AP2γ acts as a regulator of basal progenitor fate, linking regional and laminar specification in the mouse developing cerebral cortex.

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Figure 1: AP2γ expression in the mouse brain.
Figure 2: Cell division and basal progenitor identity in the cerebral cortex of AP2γ−/− mice at mid-neurogenesis.
Figure 3: Regulation of basal progenitor transcripts by AP2γ.
Figure 4: AP2γ overexpression in the developing cortex.
Figure 5: Upper layer neuron defects in adult AP2γ−/− mice.
Figure 6: Neurogenesis at E14 in the cerebral cortex of AP2γ−/− mice.
Figure 7: Visual physiology of wild-type and AP2γ−/− cortices.

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EMBL/GenBank/DDBJ

Gene Expression Omnibus

Change history

  • 25 September 2009

    In the version of this article initially published, one of the corresponding authors’ email addresses was misspelled. It should be luisapinto@ecsaude.uminho.pt. In addition, errors occurred in some of the numbers listed in the last subsection of the Results section. Instead of “Notably, AP2γ−/− mice also showed alterations in cortical binocularity (Fig. 7c,d and Supplementary Table 2) and a tendency toward an increased latency of visual response (wild type = 109.95 ms, AP2γ/− = 127.19 ms; Supplementary Table 2). […] Indeed, monocular deprivation for 3 d caused a significant change in binocularity in adult AP2γ−/− (P = 0.027), but not wild-type (P = 0.365), mice (Fig. 7d),” the affected sentences should read, “Notably, AP2γ−/− mice also showed alterations in cortical binocularity (Fig. 7c,d and Supplementary Table 2) and a tendency toward an increased latency of visual response (wild type = 110.0 ± 3.8 ms, AP2γ−/− = 127.2 ± 6.4 ms; t-test, P = 0.05; Supplementary Table 2). […] Indeed, monocular deprivation for 3 d caused a significant change in binocularity in adult AP2γ−/− (P = 0.01), but not wild-type (P = 0.365), mice (Fig. 7d).” The errors have been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Rash, B.G. & Grove, E.A. Area and layer patterning in the developing cerebral cortex. Curr. Opin. Neurobiol. 16, 25–34 (2006).

  2. 2

    O'Leary, D.D., Chou, S.J. & Sahara, S. Area patterning of the mammalian cortex. Neuron 56, 252–269 (2007).

  3. 3

    Molyneaux, B.J., Arlotta, P., Menezes, J.R. & Macklis, J.D. Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8, 427–437 (2007).

  4. 4

    Sur, M. & Rubenstein, J.L. Patterning and plasticity of the cerebral cortex. Science 310, 805–810 (2005).

  5. 5

    Polleux, F., Dehay, C., Goffinet, A. & Kennedy, H. Pre- and post-mitotic events contribute to the progressive acquisition of area-specific connectional fate in the neocortex. Cereb. Cortex 11, 1027–1039 (2001).

  6. 6

    Dehay, C. & Kennedy, H. Cell-cycle control and cortical development. Nat. Rev. Neurosci. 8, 438–450 (2007).

  7. 7

    Götz, M. & Huttner, W.B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788 (2005).

  8. 8

    Haubensak, W., Attardo, A., Denk, W. & Huttner, W.B. Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc. Natl. Acad. Sci. USA 101, 3196–3201 (2004).

  9. 9

    Miyata, T. et al. Asymmetric production of surface-dividing and non–surface dividing cortical progenitor cells. Development 131, 3133–3145 (2004).

  10. 10

    Noctor, S.C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A.R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136–144 (2004).

  11. 11

    Wu, S.X. et al. Pyramidal neurons of upper cortical layers generated by NEX-positive progenitor cells in the subventricular zone. Proc. Natl. Acad. Sci. USA 102, 17172–17177 (2005).

  12. 12

    Martínez-Cerdeño, V., Noctor, S.C. & Kriegstein, A.R. The role of intermediate progenitor cells in the evolutionary expansion of the cerebral cortex. Cereb. Cortex 16, 152–161 (2006).

  13. 13

    Lukaszewicz, A. et al. The concerted modulation of proliferation and migration contributes to the specification of the cytoarchitecture and dimensions of cortical areas. Cereb. Cortex 16 (Suppl 1): i26–i34 (2006).

  14. 14

    Nieto, M. et al. Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II–IV of the cerebral cortex. J. Comp. Neurol. 479, 168–180 (2004).

  15. 15

    Zimmer, C., Tiveron, M.C., Bodmer, R. & Cremer, H. Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons. Cereb. Cortex 14, 1408–1420 (2004).

  16. 16

    Tarabykin, V., Stoykova, A., Usman, N. & Gruss, P. Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128, 1983–1993 (2001).

  17. 17

    Cubelos, B. et al. Cux-2 controls the proliferation of neuronal intermediate precursors of the cortical subventricular zone. Cereb. Cortex 18, 1758–1770 (2008).

  18. 18

    Kowalczyk, T. et al. Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex. Cereb. Cortex published online, doi:10.1093/cercor/bhn260 (23 January 2009).

  19. 19

    Sessa, A., Mao, C.A., Hadjantonakis, A.K., Klein, W.H. & Broccoli, V. Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron 60, 56–69 (2008).

  20. 20

    Arnold, S.J. et al. The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone. Genes Dev. 22, 2479–2484 (2008).

  21. 21

    Pinto, L. et al. Prospective isolation of functionally distinct radial glial subtypes—lineage and transcriptome analysis. Mol. Cell Neurosci. 38, 15–42 (2008).

  22. 22

    Götz, M., Stoykova, A. & Gruss, P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031–1044 (1998).

  23. 23

    Englund, C. et al. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells and postmitotic neurons in developing neocortex. J. Neurosci. 25, 247–251 (2005).

  24. 24

    Haubst, N. et al. Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development. Development 131, 6131–6140 (2004).

  25. 25

    Stoykova, A., Treichel, D., Hallonet, M. & Gruss, P. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050 (2000).

  26. 26

    Kroll, T.T. & O'Leary, D.D. Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate. Proc. Natl. Acad. Sci. USA 102, 7374–7379 (2005).

  27. 27

    Holm, P.C. et al. Loss- and gain-of-function analyses reveal targets of Pax6 in the developing mouse telencephalon. Mol. Cell. Neurosci. 34, 99–119 (2007).

  28. 28

    Werling, U. & Schorle, H. Transcription factor gene AP-2 gamma essential for early murine development. Mol. Cell. Biol. 22, 3149–3156 (2002).

  29. 29

    Zhao, F., Lufkin, T. & Gelb, B.D. Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis. Gene Expr. Patterns 3, 213–217 (2003).

  30. 30

    Chazaud, C. et al. AP-2.2, a novel gene related to AP-2, is expressed in the forebrain, limbs and face during mouse embryogenesis. Mech. Dev. 54, 83–94 (1996).

  31. 31

    Iwasato, T. et al. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406, 726–731 (2000).

  32. 32

    Werling, U. & Schorle, H. Conditional inactivation of transcription factor AP-2gamma by using the Cre/loxP recombination system. Genesis 32, 127–129 (2002).

  33. 33

    Ferrere, A., Vitalis, T., Gingras, H., Gaspar, P. & Cases, O. Expression of Cux-1 and Cux-2 in the developing somatosensory cortex of normal and barrel-defective mice. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 288, 158–165 (2006).

  34. 34

    Roy, K. et al. The Tlx gene regulates the timing of neurogenesis in the cortex. J. Neurosci. 24, 8333–8345 (2004).

  35. 35

    Gillies, K. & Price, D.J. The fates of cells in the developing cerebral cortex of normal and methylazoxymethanol acetate-lesioned mice. Eur. J. Neurosci. 5, 73–84 (1993).

  36. 36

    Gianfranceschi, L., Fiorentini, A. & Maffei, L. Behavioural visual acuity of wild type and bcl2 transgenic mouse. Vision Res. 39, 569–574 (1999).

  37. 37

    Fagiolini, M., Pizzorusso, T., Berardi, N., Domenici, L. & Maffei, L. Functional postnatal development of the rat primary visual cortex and the role of visual experience: dark rearing and monocular deprivation. Vision Res. 34, 709–720 (1994).

  38. 38

    Li, H., Goswami, P.C. & Domann, F.E. AP-2gamma induces p21 expression, arrests cell cycle, and inhibits the tumor growth of human carcinoma cells. Neoplasia 8, 568–577 (2006).

  39. 39

    Farkas, L.M. et al. Insulinoma-associated 1 has a panneurogenic role and promotes the generation and expansion of basal progenitors in the developing mouse neocortex. Neuron 60, 40–55 (2008).

  40. 40

    Mattar, P. et al. Basic helix-loop-helix transcription factors cooperate to specify a cortical projection neuron identity. Mol. Cell. Biol. 28, 1456–1469 (2008).

  41. 41

    Fan, G. et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345–3356 (2005).

  42. 42

    Kim, E.A. et al. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J. Biol. Chem. 281, 7489–7497 (2006).

  43. 43

    Cundiff, P. et al. ERK5 MAP kinase regulates Neurogenin1 during cortical neurogenesis. PLoS One 4, e5204 (2009).

  44. 44

    Schuurmans, C. et al. Sequential phases of cortical specification involve neurogenin-dependent and -independent pathways. EMBO J. 23, 2892–2902 (2004).

  45. 45

    Cancedda, L. et al. Acceleration of visual system development by environmental enrichment. J. Neurosci. 24, 4840–4848 (2004).

  46. 46

    Spolidoro, M., Sale, A., Berardi, N. & Maffei, L. Plasticity in the adult brain: lessons from the visual system. Exp. Brain Res. 192, 335–341 (2008).

  47. 47

    Caleo, M. et al. Transient synaptic silencing of developing striate cortex has persistent effects on visual function and plasticity. J. Neurosci. 27, 4530–4540 (2007).

  48. 48

    Costa, M.R., Bucholz, O., Schroeder, T. & Gotz, M. Late origin of glia-restricted progenitors in the developing mouse cerebral cortex. Cereb. Cortex 19, 135–143 (2009).

  49. 49

    Hand, R. et al. Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48, 45–62 (2005).

  50. 50

    Porciatti, V., Pizzorusso, T. & Maffei, L. The visual physiology of the wild-type mouse determined with pattern VEPs. Vision Res. 39, 3071–3081 (1999).

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Acknowledgements

We are very grateful to M. Moser, S. Pfaff, C. Schuurmans and Y. Gotoh for in situ probes and to R. Jäger for providing reagents. We thank T. Öztürk, A. Steiner, A. Waiser and D. Franzen for excellent technical assistance. H.S. was supported by the Deutsche Forschungsgemeinschaft. M.G. was supported by the Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung and the Bavarian government. L.P. is supported by the Portuguese Fundaçäo para a Ciência e Tecnologia/European Social Fund.

Author information

L.P. did most of the experimental work. D.D. contributed to the in vitro studies and to immunostaining in the embryonic cortex. M.-T.S. contributed to the in utero injections. J.N. contributed to the luciferase assay. M.I. and J.B. conducted the microarrays analyses. M.S.B. contributed to the beads injections. L.R., L.G., C.C. and M.C. conducted the visual functional analysis. S.N.W. and H.S. generated the AP2γ conditional knockout mice. V.T. contributed with antibodies. K.B. conducted the adult human analysis. F.G. prepared the Mash1 construct and provided the Ngn2KiMash1 mice. N.Z. conducted the embryonic human analyses. C.D. conducted the embryonic monkey analyses. M.G. supervised the project and wrote the manuscript together with L.P.

Correspondence to Luisa Pinto or Magdalena Götz.

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Supplementary Figures 1–13, Supplementary Tables 1 and 2 (PDF 7056 kb)

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Pinto, L., Drechsel, D., Schmid, M. et al. AP2γ regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex. Nat Neurosci 12, 1229–1237 (2009). https://doi.org/10.1038/nn.2399

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