Elizabeth Grove

Research Summary
Determining the mechanisms of cerebral cortical development is essential to understanding the functions, disorders, and evolution of the brain. My research focuses on the embryonic and early postnatal development of cerebral cortex in the mouse. Specific questions include: how part of the embryonic neuroepithelium is divided, or “patterned” into the neocortex and hippocampus; how different hippocampal neuronal cell types are specified; and how a consistent map of functionally distinct areas is laid out in neocortex. To a developmental biologist the cerebral cortex may seem too complex a system for studies of tissue patterning and cell type specification. My lab, however, has contributed to a model in which the embryonic cortex is initially patterned by secreted signaling molecules, including Fibroblast Growth Factor (FGF) 8, and the Wnt protein, Wnt3a, together with downstream transcription factors, in much the same way as in the rest of the embryo. FGF8 disperses from an anterior source to establish the anterior to posterior (A/P) axis of the neocortical area map. Wnt3a influences the medial to lateral (M/L) axis and is also required for development of the hippocampus. Together, FGF8 and Wnt3a shape expression gradients of transcription factor genes that control the size and position of neocortical areas as well as hippocampal growth. This model is still incomplete. For example, how sharp area boundaries arise from graded gene expression is unclear. Classically, for this step, a mechanism specific to the nervous system is proposed, namely the growth of axons from the thalamus into the neocortex. Yet previous findings indicate that precise guidance cues lie within nascent neocortical areas. To identify area-specific axon guidance molecules, we plan to harvest in cells from a mouse in which sensory areas are marked by green fluorescence, and compare the transcriptomes of different areas using RNA-Seq. A major outstanding task is to determine if our model of cortical patterning, based on studies of the mouse, holds for larger, multi-folded (gyrencephalic) brains of carnivores and primates. Common features of the area map, conserved across mammals, suggest the model could generalize, and early evidence from a study of the gyrencephalic ferret supports this hypothesis. Methods: Candidate genes are identified and their function altered using mouse genetics and a fine-scale method of in utero microelectroporation that we pioneered. The cortical phenotype of mice in which gene function is altered is analyzed by area-specific gene and protein expression and connectivity, and occasionally by behavior. We discovered, for instance, that part of the hippocampus is shrunken in mice deficient in BMP signaling, and that these mice were "fearless" in situations that would normally induce anxiety, supporting a new view of hippocampal function. Cell type specific transcriptomes will be identified with single cell RNA-Seq.
Keywords
Neurobiology, Developmental Biology, Neocortex, Neocortical area map, Hippocampus, Embryonic Pattern Formation, Developmental Gene Expression Regulation, Developmental Disabilities, Gene Expression Regulation
Education
  • Yale, New Haven, Ct, BA Philosopy 06/1977
  • M.I.T, Boston, MA, PhD Neuroscience 06/1987
  • University College, London, London UK, postdoc Neurophysiology 01/1989
  • National Institute forf Medical Research, Mill Hill, London,UK, post0doc Developmental Neurobiology 12/1993
Biosciences Graduate Program Association
Awards & Honors
  • 2003 - 2008 Associate Editor Journal of Neuroscience
  • 2003 - Special Lecture, Society for Neuroscience Annual Meeting Society for Neuroscience
  • 2004 - 2014 MERIT award from NIMH NIMH
  • 2005 - Speaker in Director's Seminar Series NIMH
  • 2010 - 2014 Editorial Board Journal of Comparative Neurology
  • 2011 - pres Board of Reviewing Editors Science
  • 2013 - 2018 Member Faculty of 1000
  • 2017 - Krieg Cortical Kudos Discoverer Award, Contribution to Understanding Cortical Development Cajal Club
Publications
  1. Jones WD, Guadiana SM, Grove EA. A model of neocortical area patterning in the lissencephalic mouse may hold for larger gyrencephalic brains. J Comp Neurol. 2019 May 15; 527(9):1461-1477. View in: PubMed

  2. Desmaris E, Keruzore M, Saulnier A, Ratié L, Assimacopoulos S, De Clercq S, Nan X, Roychoudhury K, Qin S, Kricha S, Chevalier C, Lingner T, Henningfeld KA, Zarkower D, Mallamaci A, Theil T, Campbell K, Pieler T, Li M, Grove EA, Bellefroid EJ. DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors. J Neurosci. 2018 10 17; 38(42):9105-9121. View in: PubMed

  3. De Clercq S, Keruzore M, Desmaris E, Pollart C, Assimacopoulos S, Preillon J, Ascenzo S, Matson CK, Lee M, Nan X, Li M, Nakagawa Y, Hochepied T, Zarkower D, Grove EA, Bellefroid EJ. DMRT5 Together with DMRT3 Directly Controls Hippocampus Development and Neocortical Area Map Formation. Cereb Cortex. 2018 02 01; 28(2):493-509. View in: PubMed

  4. de Frutos CA, Bouvier G, Arai Y, Thion MS, Lokmane L, Keita M, Garcia-Dominguez M, Charnay P, Hirata T, Riethmacher D, Grove EA, Tissir F, Casado M, Pierani A, Garel S. Reallocation of Olfactory Cajal-Retzius Cells Shapes Neocortex Architecture. Neuron. 2016 Oct 19; 92(2):435-448. View in: PubMed

  5. Ruiz-Reig N, Andrés B, Huilgol D, Grove EA, Tissir F, Tole S, Theil T, Herrera E, Fairén A. Lateral Thalamic Eminence: A Novel Origin for mGluR1/Lot Cells. Cereb Cortex. 2017 05 01; 27(5):2841-2856. View in: PubMed

  6. Qu Y, Huang Y, Feng J, Alvarez-Bolado G, Grove EA, Yang Y, Tissir F, Zhou L, Goffinet AM. Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner. Proc Natl Acad Sci U S A. 2014 Jul 22; 111(29):E2996-3004. View in: PubMed

  7. Caronia-Brown G, Yoshida M, Gulden F, Assimacopoulos S, Grove EA. The cortical hem regulates the size and patterning of neocortex. Development. 2014 Jul; 141(14):2855-65. View in: PubMed

  8. Deck M, Lokmane L, Chauvet S, Mailhes C, Keita M, Niquille M, Yoshida M, Yoshida Y, Lebrand C, Mann F, Grove EA, Garel S. Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections. Neuron. 2013 Feb 06; 77(3):472-84. View in: PubMed

  9. Assimacopoulos S, Kao T, Issa NP, Grove EA. Fibroblast growth factor 8 organizes the neocortical area map and regulates sensory map topography. J Neurosci. 2012 May 23; 32(21):7191-201. View in: PubMed

  10. Pani AM, Mullarkey EE, Aronowicz J, Assimacopoulos S, Grove EA, Lowe CJ. Ancient deuterostome origins of vertebrate brain signalling centres. Nature. 2012 Mar 14; 483(7389):289-94. View in: PubMed

  11. Rash BG, Grove EA. Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain. Dev Biol. 2011 Nov 15; 359(2):242-50. View in: PubMed

  12. Grove EA. Wnt signaling meets internal dissent. Genes Dev. 2011 Sep 01; 25(17):1759-62. View in: PubMed

  13. Louvi A, Grove EA. Cilia in the CNS: the quiet organelle claims center stage. Neuron. 2011 Mar 24; 69(6):1046-60. View in: PubMed

  14. Toyoda R, Assimacopoulos S, Wilcoxon J, Taylor A, Feldman P, Suzuki-Hirano A, Shimogori T, Grove EA. FGF8 acts as a classic diffusible morphogen to pattern the neocortex. Development. 2010 Oct; 137(20):3439-48. View in: PubMed

  15. Caronia-Brown G, Grove EA. Timing of cortical interneuron migration is influenced by the cortical hem. Cereb Cortex. 2011 Apr; 21(4):748-55. View in: PubMed

  16. Caronia G, Wilcoxon J, Feldman P, Grove EA. Bone morphogenetic protein signaling in the developing telencephalon controls formation of the hippocampal dentate gyrus and modifies fear-related behavior. J Neurosci. 2010 May 05; 30(18):6291-301. View in: PubMed

  17. Grove EA. Turning neurons into a nervous system. Development. 2008 Jul; 135(13):2203-6. View in: PubMed

  18. Grove EA. Neuroscience. Organizing the source of memory. Science. 2008 Jan 18; 319(5861):288-9. View in: PubMed

  19. Rash BG, Grove EA. Patterning the dorsal telencephalon: a role for sonic hedgehog? J Neurosci. 2007 Oct 24; 27(43):11595-603. View in: PubMed

  20. Louvi A, Yoshida M, Grove EA. The derivatives of the Wnt3a lineage in the central nervous system. J Comp Neurol. 2007 Oct 10; 504(5):550-69. View in: PubMed

  21. Rash BG, Grove EA. Area and layer patterning in the developing cerebral cortex. Curr Opin Neurobiol. 2006 Feb; 16(1):25-34. View in: PubMed

  22. Yoshida M, Assimacopoulos S, Jones KR, Grove EA. Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order. Development. 2006 Feb; 133(3):537-45. View in: PubMed

  23. Grove EA. Local axon guidance in cerebral cortex and thalamus: are we there yet? Neuron. 2005 Nov 23; 48(4):522-4. View in: PubMed

  24. Shimogori T, Grove EA. Fibroblast growth factor 8 regulates neocortical guidance of area-specific thalamic innervation. J Neurosci. 2005 Jul 13; 25(28):6550-60. View in: PubMed

  25. Belmadani A, Tran PB, Ren D, Assimacopoulos S, Grove EA, Miller RJ. The chemokine stromal cell-derived factor-1 regulates the migration of sensory neuron progenitors. J Neurosci. 2005 Apr 20; 25(16):3995-4003. View in: PubMed

  26. Shimogori T, Banuchi V, Ng HY, Strauss JB, Grove EA. Embryonic signaling centers expressing BMP, WNT and FGF proteins interact to pattern the cerebral cortex. Development. 2004 Nov; 131(22):5639-47. View in: PubMed

  27. Grove EA. Patterning the developing cerebral cortex. Curr Biol. 1992 Mar; 2(3):142-4. View in: PubMed

  28. Abu-Khalil A, Fu L, Grove EA, Zecevic N, Geschwind DH. Wnt genes define distinct boundaries in the developing human brain: implications for human forebrain patterning. J Comp Neurol. 2004 Jun 21; 474(2):276-88. View in: PubMed

  29. Louvi A, Sisodia SS, Grove EA. Presenilin 1 in migration and morphogenesis in the central nervous system. Development. 2004 Jul; 131(13):3093-105. View in: PubMed

  30. Shimogori T, VanSant J, Paik E, Grove EA. Members of the Wnt, Fz, and Frp gene families expressed in postnatal mouse cerebral cortex. J Comp Neurol. 2004 Jun 07; 473(4):496-510. View in: PubMed

  31. Grove EA, Fukuchi-Shimogori T. Generating the cerebral cortical area map. Annu Rev Neurosci. 2003; 26:355-80. View in: PubMed

  32. Assimacopoulos S, Grove EA, Ragsdale CW. Identification of a Pax6-dependent epidermal growth factor family signaling source at the lateral edge of the embryonic cerebral cortex. J Neurosci. 2003 Jul 23; 23(16):6399-403. View in: PubMed

  33. Fukuchi-Shimogori T, Grove EA. Emx2 patterns the neocortex by regulating FGF positional signaling. Nat Neurosci. 2003 Aug; 6(8):825-31. View in: PubMed

  34. McClintock JM, Jozefowicz C, Assimacopoulos S, Grove EA, Louvi A, Prince VE. Conserved expression of Hoxa1 in neurons at the ventral forebrain/midbrain boundary of vertebrates. Dev Genes Evol. 2003 Aug; 213(8):399-406. View in: PubMed

  35. Ligon KL, Echelard Y, Assimacopoulos S, Danielian PS, Kaing S, Grove EA, McMahon AP, Rowitch DH. Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Development. 2003 May; 130(10):2275-87. View in: PubMed

  36. Grove E. The telencephalon saved by TLC. Neuron. 2002 Jul 18; 35(2):215-7. View in: PubMed

  37. Lu M, Grove EA, Miller RJ. Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A. 2002 May 14; 99(10):7090-5. View in: PubMed

  38. Fukuchi-Shimogori T, Grove EA. Neocortex patterning by the secreted signaling molecule FGF8. Science. 2001 Nov 02; 294(5544):1071-4. View in: PubMed

  39. Tole S, Grove EA. Detailed field pattern is intrinsic to the embryonic mouse hippocampus early in neurogenesis. J Neurosci. 2001 Mar 01; 21(5):1580-9. View in: PubMed

  40. Ragsdale CW, Grove EA. Patterning the mammalian cerebral cortex. Curr Opin Neurobiol. 2001 Feb; 11(1):50-8. View in: PubMed

  41. Bulchand S, Grove EA, Porter FD, Tole S. LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem. Mech Dev. 2001 Feb; 100(2):165-75. View in: PubMed

  42. Tole S, Goudreau G, Assimacopoulos S, Grove EA. Emx2 is required for growth of the hippocampus but not for hippocampal field specification. J Neurosci. 2000 Apr 01; 20(7):2618-25. View in: PubMed

  43. Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000 Feb; 127(3):457-67. View in: PubMed

  44. Tole S, Ragsdale CW, Grove EA. Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes(J). Dev Biol. 2000 Jan 15; 217(2):254-65. View in: PubMed

  45. Grove EA, Tole S. Patterning events and specification signals in the developing hippocampus. Cereb Cortex. 1999 Sep; 9(6):551-61. View in: PubMed

  46. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW. The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development. 1998 Jun; 125(12):2315-25. View in: PubMed

  47. Tole S, Christian C, Grove EA. Early specification and autonomous development of cortical fields in the mouse hippocampus. Development. 1997 Dec; 124(24):4959-70. View in: PubMed

  48. Price J, Grove E, Williams B, Hajihosseini M, Iavachev L, McNaughton L, Götz M. Labelling neural precursor cells with retroviruses. Gene Ther. 1994; 1 Suppl 1:S4-5. View in: PubMed

  49. Grove EA, Williams BP, Li DQ, Hajihosseini M, Friedrich A, Price J. Multiple restricted lineages in the embryonic rat cerebral cortex. Development. 1993 Feb; 117(2):553-61. View in: PubMed

  50. Davis HP, Rosenzweig MR, Grove EA, Bennett EL. Investigation of the reported protective effect of cycloheximide on memory. Pharmacol Biochem Behav. 1984 Mar; 20(3):405-13. View in: PubMed

  51. Haber SN, Groenewegen HJ, Grove EA, Nauta WJ. Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway. J Comp Neurol. 1985 May 15; 235(3):322-35. View in: PubMed

  52. Grove EA. Efferent connections of the substantia innominata in the rat. J Comp Neurol. 1988 Nov 15; 277(3):347-64. View in: PubMed

  53. Grove EA. Neural associations of the substantia innominata in the rat: afferent connections. J Comp Neurol. 1988 Nov 15; 277(3):315-46. View in: PubMed

  54. Price J, Williams B, Grove E. Cell lineage in the cerebral cortex. Dev Suppl. 1991; Suppl 2:23-8. View in: PubMed

  55. Price J, Williams B, Moore R, Read J, Grove E. Analysis of cell lineage in the rat cerebral cortex. Ann N Y Acad Sci. 1991; 633:56-63. View in: PubMed

  56. Grove EA, Kirkwood TB, Price J. Neuronal precursor cells in the rat hippocampal formation contribute to more than one cytoarchitectonic area. Neuron. 1992 Feb; 8(2):217-29. View in: PubMed

  57. Kirkwood TB, Price J, Grove EA. The dispersion of neuronal clones across the cerebral cortex. Science. 1992 Oct 09; 258(5080):317-20. View in: PubMed

  58. Price J, Williams B, Grove E. The generation of cellular diversity in the cerebral cortex. Brain Pathol. 1992 Jan; 2(1):23-9. View in: PubMed