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Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala

Abstract

The development of the amygdala, a central structure of the limbic system, remains poorly understood. We found that two spatially distinct and early-specified telencephalic progenitor pools marked by the homeodomain transcription factor Dbx1 are major sources of neuronal cell diversity in the mature mouse amygdala. We found that Dbx1-positive cells of the ventral pallium generate the excitatory neurons of the basolateral complex and cortical amygdala nuclei. Moreover, Dbx1-derived cells comprise a previously unknown migratory stream that emanates from the preoptic area (POA), a ventral telencephalic domain adjacent to the diencephalic border. The Dbx1-positive, POA-derived population migrated specifically to the amygdala and, as defined by both immunochemical and electrophysiological criteria, generated a unique subclass of inhibitory neurons in the medial amygdala nucleus. Thus, this POA-derived population represents a previously unknown progenitor pool dedicated to the limbic system.

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Figure 1: Expression of Dbx1 and knock-in approach.
Figure 2: Dbx1-derived cells in the postnatal amygdala.
Figure 3: Dbx1-derived cells in the developing basal telencephalon.
Figure 4: Distribution of YFP-positive recombined cells at embryonic stages.
Figure 5: Migration from the PSB and POA.
Figure 6: Dbx1-derived cells express regional cell fate markers during embryogenesis.
Figure 7: Dbx1-positive progenitors generate amygdala excitatory and inhibitory neurons.
Figure 8: Electrophysiological properties of Dbx1-derived medial amygdala neurons.

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References

  1. Alheid, G.F. Extended amygdala and basal forebrain. Ann. NY Acad. Sci. 985, 185–205 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Sah, P., Faber, E.S., Lopez De Armentia, M. & Power, J. The amygdaloid complex: anatomy and physiology. Physiol. Rev. 83, 803–834 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Swanson, L.W. & Petrovich, G.D. What is the amygdala? Trends Neurosci. 21, 323–331 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Amaral, D.G., Bauman, M.D. & Schumann, C.M. The amygdala and autism: implications from nonhuman primate studies. Genes Brain Behav. 2, 295–302 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Baron-Cohen, S. et al. The amygdala theory of autism. Neurosci. Biobehav. Rev. 24, 355–364 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Rauch, S.L., Shin, L.M. & Phelps, E.A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research–past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

    Article  PubMed  Google Scholar 

  7. Bai, J. et al. The role of DCX and LIS1 in migration through the lateral cortical stream of developing forebrain. Dev. Neurosci. 30, 144–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Carney, R.S. et al. Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system. J. Neurosci. 26, 11562–11574 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Medina, L. et al. Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the developing mouse claustroamygdaloid complex. J. Comp. Neurol. 474, 504–523 (2004).

    Article  PubMed  Google Scholar 

  10. Stenman, J., Toresson, H. & Campbell, K. Identification of two distinct progenitor populations in the lateral ganglionic eminence: implications for striatal and olfactory bulb neurogenesis. J. Neurosci. 23, 167–174 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bielle, F. et al. Multiple origins of Cajal-Retzius cells at the borders of the developing pallium. Nat. Neurosci. 8, 1002–1012 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Yun, K., Potter, S. & Rubenstein, J.L. Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128, 193–205 (2001).

    CAS  PubMed  Google Scholar 

  13. Carney, R.S.E., Cocas, L.A., Hirata, T., Mansfield, K. & Corbin, J.G. Differential regulation of telencephalic pallial–subpallial boundary patterning by Pax6 and Gsh2. Cereb. Cortex published online, doi:10.1093/cercor/bhn123 (12 August 2008).

  14. Tao, W. & Lai, E. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8, 957–966 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Branda, C.S. & Dymecki, S.M. Talking about a revolution: the impact of site-specific recombinases on genetic analyses in mice. Dev. Cell 6, 7–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Joyner, A.L. & Zervas, M. Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev. Dyn. 235, 2376–2385 (2006).

    Article  PubMed  Google Scholar 

  17. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K. & McMahon, A.P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8, 1323–1326 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Pierani, A. et al. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29, 367–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hevner, R.F. et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29, 353–366 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Porteus, M.H., Bulfone, A., Ciaranello, R.D. & Rubenstein, J.L. Isolation and characterization of a novel cDNA clone encoding a homeodomain that is developmentally regulated in the ventral forebrain. Neuron 7, 221–229 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. del Rio, M.R. & DeFelipe, J. Colocalization of calbindin D-28k, calretinin and GABA immunoreactivities in neurons of the human temporal cortex. J. Comp. Neurol. 369, 472–482 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. McDonald, A.J. & Mascagni, F. Colocalization of calcium-binding proteins and GABA in neurons of the rat basolateral amygdala. Neuroscience 105, 681–693 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Olmos, J.L., Real, M.A., Medina, L., Guirado, S. & Davila, J.C. Distribution of nitric oxide–producing neurons in the developing and adult mouse amygdalar basolateral complex. Brain Res. Bull. 66, 465–469 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Tanaka, M. et al. Nitrergic neurons in the medial amygdala project to the hypothalamic paraventricular nucleus of the rat. Brain Res. 777, 13–21 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Fuentealba, P. et al. Ivy cells: a population of nitric oxide–producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57, 917–929 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, Y. et al. Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J. Physiol. (Lond.) 561, 65–90 (2004).

    Article  CAS  Google Scholar 

  30. Beierlein, M., Gibson, J.R. & Connors, B.W. Two dynamically distinct inhibitory networks in layer 4 of the neocortex. J. Neurophysiol. 90, 2987–3000 (2003).

    Article  PubMed  Google Scholar 

  31. Bacci, A., Rudolph, U., Huguenard, J.R. & Prince, D.A. Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses. J. Neurosci. 23, 9664–9674 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bacci, A., Huguenard, J.R. & Prince, D.A. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Bian, X., Yanagawa, Y., Chen, W.R. & Luo, M. Cortical-like functional organization of the pheromone-processing circuits in the medial amygdala. J. Neurophysiol. 99, 77–86 (2008).

    Article  PubMed  Google Scholar 

  34. Corbin, J.G., Nery, S. & Fishell, G. Telencephalic cells take a tangent: nonradial migration in the mammalian forebrain. Nat. Neurosci. 4 Suppl: 1177–1182 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Marin, O. & Rubenstein, J.L. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Corbin, J.G. et al. Regulation of neural progenitor cell development in the nervous system. J. Neurochem. 106, 2272–2287 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Flames, N. et al. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci. 27, 9682–9695 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Choi, G.B. et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 46, 647–660 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Molnar, Z. & Butler, A.B. The corticostriatal junction: a crucial region for forebrain development and evolution. Bioessays 24, 530–541 (2002).

    Article  PubMed  Google Scholar 

  40. Waclaw, R.R. et al. The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons. Neuron 49, 503–516 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Stoykova, A., Fritsch, R., Walther, C. & Gruss, P. Forebrain patterning defects in Small eye mutant mice. Development 122, 3453–3465 (1996).

    CAS  PubMed  Google Scholar 

  42. Toresson, H., Potter, S.S. & Campbell, K. Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).

    CAS  PubMed  Google Scholar 

  43. Tole, S., Remedios, R., Saha, B. & Stoykova, A. Selective requirement of Pax6, but not Emx2, in the specification and development of several nuclei of the amygdaloid complex. J. Neurosci. 25, 2753–2760 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gorski, J.A. et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nery, S., Fishell, G. & Corbin, J.G. The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nat. Neurosci. 5, 1279–1287 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Marin, O., Anderson, S.A. & Rubenstein, J.L. Origin and molecular specification of striatal interneurons. J. Neurosci. 20, 6063–6076 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu, Q., Tam, M. & Anderson, S.A. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506, 16–29 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Remedios, R. et al. A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex. Nat. Neurosci. 10, 1141–1150 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Garcia-Lopez, M. et al. Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development. J. Comp. Neurol. 506, 46–74 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Corbin, J.G., Gaiano, N., Machold, R.P., Langston, A. & Fishell, G. The Gsh2 homeodomain gene controls multiple aspects of telencephalic development. Development 127, 5007–5020 (2000).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank members of the Corbin, Haydar and Zohn laboratories for input during various stages of this project, with a special acknowledgment to J.L. Olmos-Serrano for his expert insight and advice on amygdala anatomy and development. We also gratefully acknowledge T. Haydar, J.L. Olmos-Serrano, I. Zohn and V. Gallo for critical reading of the manuscript. We thank R. Hevner for the Tbr1 antibody (University of Washington), S. Aizawa for the Foxg1 and Lhx2 probes (RIKEN) and M. Matise for the Dbx1 probe (University of Medicine and Dentistry New Jersey/Robert Wood Johnson Medical School). The RC2 monoclonal antibody was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the US National Institute of Child Health and Human Development and maintained by the University of Iowa. We also thank the Children's National Medical Center and Georgetown University Transgenic Cores for the generation of mice. This work was supported by grants from the US National Institutes of Health (J.G.C. and M.M.H.). The Children's National Medical Center microscope core facility is supported by an US National Institutes of Health Intellectual and Developmental Disabilities Research Center grant.

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T.H. generated the Dbx1+/CreERT2 knock-in animals and carried out the fate mapping, slice culture assays, immunohistochemistry and in situ hybridization analysis. G.M.L. provided timed crossed Dbx1+/LacZ embryos and input on the analysis. L.A.C. provided technical assistance for the slice culture migration assays and analysis. P.L. and M.M.H. obtained and analyzed the electrophysiological and biocytin data. J.G.C. carried out the matrigel experiments. The study was conceived and planned by T.H. and J.G.C. The majority of the manuscript was written by T.H. and J.G.C. with the electrophysiology part being written by M.M.H.

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Correspondence to Joshua G Corbin.

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Hirata, T., Li, P., Lanuza, G. et al. Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala. Nat Neurosci 12, 141–149 (2009). https://doi.org/10.1038/nn.2241

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