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Ontogenetic establishment of order-specific nuclear organization in the mammalian thalamus

Nature Neuroscience volume 20, pages 516528 (2017) | Download Citation

Abstract

The thalamus connects the cortex with other brain regions and supports sensory perception, movement, and cognitive function via numerous distinct nuclei. However, the mechanisms underlying the development and organization of diverse thalamic nuclei remain largely unknown. Here we report an intricate ontogenetic logic of mouse thalamic structures. Individual radial glial progenitors in the developing thalamus actively divide and produce a cohort of neuronal progeny that shows striking spatial configuration and nuclear occupation related to functionality. Whereas the anterior clonal cluster displays relatively more tangential dispersion and contributes predominantly to nuclei with cognitive functions, the medial ventral posterior clonal cluster forms prominent radial arrays and contributes mostly to nuclei with sensory- or motor-related activities. Moreover, the first-order and higher-order sensory and motor nuclei across different modalities are largely segregated clonally. Notably, sonic hedgehog signaling activity influences clonal spatial distribution. Our study reveals lineage relationship to be a critical regulator of nonlaminated thalamus development and organization.

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References

  1. 1.

    The Thalamus (Cambridge University Press, 2007).

  2. 2.

    & The functional states of the thalamus and the associated neuronal interplay. Physiol. Rev. 68, 649–742 (1988).

  3. 3.

    & Exploring the Thalamus and its Role in Cortical Function (MIT Press, 2006).

  4. 4.

    Thalamus plays a central role in ongoing cortical functioning. Nat. Neurosci. 19, 533–541 (2016).

  5. 5.

    , & Specification of neocortical areas and thalamocortical connections. Annu. Rev. Neurosci. 17, 419–439 (1994).

  6. 6.

    et al. A comprehensive thalamocortical projection map at the mesoscopic level. Nat. Neurosci. 17, 1276–1285 (2014).

  7. 7.

    et al. A mesoscale connectome of the mouse brain. Nature 508, 207–214 (2014).

  8. 8.

    & Functional Connetions of Cortical Areas (MIT Press, 2013).

  9. 9.

    & Building a bridal chamber: development of the thalamus. Trends Neurosci. 33, 373–380 (2010).

  10. 10.

    & Diversity of thalamic progenitor cells and postmitotic neurons. Eur. J. Neurosci. 35, 1554–1562 (2012).

  11. 11.

    , , , & GABAergic neurons in mammalian thalamus: a marker of thalamic complexity? Brain Res. Bull. 42, 27–37 (1997).

  12. 12.

    et al. Characterization of progenitor domains in the developing mouse thalamus. J. Comp. Neurol. 505, 73–91 (2007).

  13. 13.

    , , , & Olig2 lineage cells generate GABAergic neurons in the prethalamic nuclei, including the zona incerta, ventral lateral geniculate nucleus and reticular thalamic nucleus. Dev. Neurosci. 33, 118–129 (2011).

  14. 14.

    Specification of cerebral cortical areas. Science 241, 170–176 (1988).

  15. 15.

    , , & Specific synapses develop preferentially among sister excitatory neurons in the neocortex. Nature 458, 501–504 (2009).

  16. 16.

    et al. Preferential electrical coupling regulates neocortical lineage-dependent microcircuit assembly. Nature 486, 113–117 (2012).

  17. 17.

    et al. Clonally related visual cortical neurons show similar stimulus feature selectivity. Nature 486, 118–121 (2012).

  18. 18.

    , , , & Inside-out radial migration facilitates lineage-dependent neocortical microcircuit assembly. Neuron 86, 1159–1166 (2015).

  19. 19.

    , & Brain state dependent activity in the cortex and thalamus. Curr. Opin. Neurobiol. 31, 133–140 (2015).

  20. 20.

    & Tuned thalamic excitation is amplified by visual cortical circuits. Nat. Neurosci. 16, 1315–1323 (2013).

  21. 21.

    & Clones in the chick diencephalon contain multiple cell types and siblings are widely dispersed. Development 122, 65–78 (1996).

  22. 22.

    , , & Cell migration in the developing chick diencephalon. Development 124, 3525–3533 (1997).

  23. 23.

    , , , & Mosaic analysis with double markers in mice. Cell 121, 479–492 (2005).

  24. 24.

    et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell 159, 775–788 (2014).

  25. 25.

    et al. Lineage-specific laminar organization of cortical GABAergic interneurons. Nat. Neurosci. 16, 1199–1210 (2013).

  26. 26.

    , , , & Temporal regulation of Cre recombinase activity in neural stem cells. Genesis 44, 233–238 (2006).

  27. 27.

    et al. Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration. Neuron 68, 695–709 (2010).

  28. 28.

    et al. Sonic hedgehog signaling controls thalamic progenitor identity and nuclei specification in mice. J. Neurosci. 29, 4484–4497 (2009).

  29. 29.

    , , & Basal progenitor cells in the embryonic mouse thalamus - their molecular characterization and the role of neurogenins and Pax6. Neural Dev. 6, 35 (2011).

  30. 30.

    , & Unveiling the diversity of thalamocortical neuron subtypes. Eur. J. Neurosci. 35, 1524–1532 (2012).

  31. 31.

    Statistical Analysis of Spatial Point Patterns (Oxford University Press, 2003).

  32. 32.

    et al. Ventral medial nucleus neurons send thalamocortical afferents more widely and more preferentially to layer 1 than neurons of the ventral anterior-ventral lateral nuclear complex in the rat. Cereb. Cortex 25, 221–235 (2015).

  33. 33.

    , & The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness. Brain Res. Brain Res. Rev. 39, 107–140 (2002).

  34. 34.

    , , & The role of Sonic hedgehog of neural origin in thalamic differentiation in the mouse. J. Neurosci. 29, 2453–2466 (2009).

  35. 35.

    , , , & Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. 18, 937–951 (2004).

  36. 36.

    & Expression patterns of homeobox and other putative regulatory genes in the embryonic mouse forebrain suggest a neuromeric organization. Trends Neurosci. 16, 472–479 (1993).

  37. 37.

    & Dynamic patterned expression of orphan nuclear receptor genes RORα and RORβ in developing mouse forebrain. Dev. Neurosci. 25, 234–244 (2003).

  38. 38.

    , , , & Organization of radial and non-radial glia in the developing rat thalamus. J. Comp. Neurol. 428, 527–542 (2000).

  39. 39.

    & Combinatorial expression patterns of LIM-homeodomain and other regulatory genes parcellate developing thalamus. J. Neurosci. 21, 2711–2725 (2001).

  40. 40.

    et al. Dynamic spatiotemporal gene expression in embryonic mouse thalamus. J. Comp. Neurol. 519, 528–543 (2011).

  41. 41.

    & Fgf8 controls regional identity in the developing thalamus. Development 135, 2873–2881 (2008).

  42. 42.

    & Patterning and compartment formation in the diencephalon. Front. Neurosci. 6, 66 (2012).

  43. 43.

    & Cognitive and perceptual functions of the visual thalamus. Neuron 71, 209–223 (2011).

  44. 44.

    et al. Thalamic nuclei convey diverse contextual information to layer 1 of visual cortex. Nat. Neurosci. 19, 299–307 (2016).

  45. 45.

    , & A new intrathalamic pathway linking modality-related nuclei in the dorsal thalamus. Nat. Neurosci. 1, 389–394 (1998).

  46. 46.

    & Inhibitory interactions between ferret thalamic reticular neurons. J. Neurophysiol. 87, 2571–2576 (2002).

  47. 47.

    , , & Two functionally distinct networks of gap junction-coupled inhibitory neurons in the thalamic reticular nucleus. J. Neurosci. 34, 13170–13182 (2014).

  48. 48.

    et al. Normal development of embryonic thalamocortical connectivity in the absence of evoked synaptic activity. J. Neurosci. 22, 10313–10323 (2002).

  49. 49.

    et al. A cross-modal genetic framework for the development and plasticity of sensory pathways. Nature 538, 96–98 (2016).

  50. 50.

    , & The regulation of corticofugal fiber targeting by retinal inputs. Cereb. Cortex 26, 1336–1348 (2016).

  51. 51.

    et al. Distinct lineage-dependent structural and functional organization of the hippocampus. Cell 157, 1552–1564 (2014).

  52. 52.

    et al. Clonal production and organization of inhibitory interneurons in the neocortex. Science 334, 480–486 (2011).

  53. 53.

    et al. The Ca2+-activated chloride channel anoctamin-2 mediates spike-frequency adaptation and regulates sensory transmission in thalamocortical neurons. Nat. Commun. 7, 13791 (2016).

  54. 54.

    et al. MHC-I and PirB upregulation in the central and peripheral nervous system following sciatic nerve injury. PLoS One 11, e0161463 (2016).

  55. 55.

    et al. vascular influence on ventral telencephalic progenitors and neocortical interneuron production. Dev. Cell 36, 624–638 (2016).

  56. 56.

    et al. Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei. Neural Dev. 6, 29 (2011).

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Acknowledgements

We thank A.L. Joyner (Memorial Sloan Kettering Cancer Center), R. Kageyama (Kyoto University), S. Hippenmeyer (The Institute of Science and Technology), and Y. Nakagawa (University of Minnesota) for providing the R26LSL-SmoM2-EYFP, Nes-CreERT2, MADM11, and Olig3-Cre mouse lines, respectively; J.N. Betley (University of Pennsylvania) for guinea pig anti-RFP antibody, and members of S.-H.S.'s laboratory for insightful discussion and input. This work was supported by the US National Institutes of Health (R01DA024681 and R01MH101382 to S.-H.S. and P30CA008748 to Memorial Sloan Kettering Cancer Center Core Facilities), the Human Frontier Science Program (RGP0053 to S.-H.S. and K.H.), and the National Natural Science Foundation of China (61572265 to Z.H. and 759881 to S.-H.S.).

Author information

Affiliations

  1. Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Wei Shi
    • , Anjin Xianyu
    • , Zhizhong Li
    •  & Song-Hai Shi
  2. Neuroscience Graduate Program, Weill Cornell Medical College, New York, New York, USA.

    • Wei Shi
    •  & Song-Hai Shi
  3. Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Medical College, New York, New York, USA.

    • Anjin Xianyu
    •  & Song-Hai Shi
  4. College of Software, Nankai University, Tianjin, China.

    • Zhi Han
  5. Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.

    • Zhi Han
    • , Xing Tang
    •  & Kun Huang
  6. Vollum Institute, Oregon Health and Science University, Portland, Oregon, USA.

    • Haining Zhong
    •  & Tianyi Mao

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Contributions

W.S. and S.-H.S. conceived the project; W.S. collected, reconstructed and analyzed MADM and retroviral labeling data with help from A.X.; Z.H., X.T., and K.H. performed NND analysis; Z.L. generated retrovirus; A.X., Z.H., and K.H. performed alignment and nuclear identity inference and clustering analysis with input from H.Z. and T.M.; H.Z. and T.M. provided thalamocortical axonal projection data; W.S. and S.-H.S wrote the paper with input from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Zhi Han or Kun Huang or Song-Hai Shi.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Spatial distribution (X/Y/Z coordinates) and nuclear occupation of labeled neurons and glia within individual RGP-derived clones.

Videos

  1. 1.

    3D rendered image of a P21 thalamic hemisphere containing an ‘mvp’ cluster clone.

    The thalamus is colored in light gray, the non-sensory/motor-related nuclei in light magenta, and the sensory/motor-related nuclei in cyan. Labeled clonally related neurons in the thalamus are represented by colored dots. A, anterior; D, dorsal; M, medial. Similar displays are used in Supplementary Movie 2.

  2. 2.

    3D rendered image of a P21 thalamic hemisphere containing an ‘a’ cluster clone.

  3. 3.

    3D rendered image of a P21 thalamic hemisphere containing an ‘mvp’ cluster clone that predominantly occupies the FO sensory/motor-related nuclei.

    The thalamus is colored in light gray, the HO nuclei in green, the FO nuclei in yellow, and the pRE/pRH/SMT nuclei in orange. Labeled clonally related neurons in the thalamus are represented by colored dots. Similar displays are used in Supplementary Movie 4.

  4. 4.

    3D rendered image of a P21 thalamic hemisphere containing an ‘md’ cluster clone that predominantly occupies the HO sensory/motor-related nuclei.

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DOI

https://doi.org/10.1038/nn.4519

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