BMP7 expression in mammalian cortical radial glial cells increases the length of the neurogenic period

Abstract

The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.

Key words： radial glia; cortical neurogenesis; cortical gliogenesis; cortical evolution; BMP7; SHH

References

1 Abu-Khalil A, Fu L, Grove EA et al. Wnt genes define distinct boundaries in the developing human brain: implications for human forebrain patterning. J Comp Neurol 2004;474:276–288.

2 Allen BL, Song JY, Izzi L et al. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell 2011;20:775–787.

3 Allen DE, Donohue KC, Cadwell CR et al. Fate mapping of neural stem cell niches reveals distinct origins of human cortical astrocytes. Science 2022;376:1441–1446.

4 Aoto K, Nishimura T, Eto K et al. Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 2002;251:320–332.

5 Baburamani AA, Vontell RT, Uus A et al. Assessment of radial glia in the frontal lobe of fetuses with Down syndrome. Acta Neuropathol Commun 2020;8:141.

6 Blaess S, Stephen D, Joyner AL. Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling. Development 2008;135:2093–2103.

7 Cardenas A, Borrell V. Molecular and cellular evolution of corticogenesis in amniotes. Cell Mol Life Sci 2020;77:1435–1460.

8 Caronia G, Wilcoxon J, Feldman P et al. Bone morphogenetic protein signaling in the developing telencephalon controls formation of the hippocampal dentate gyrus and modifies fear-related behavior. J Neurosci 2010;30:6291–6301.

9 Caronia-Brown G, Yoshida M, Gulden F et al. The cortical hem regulates the size and patterning of neocortex. Development 2014;141:2855–2865.

10 Clegg CH, Correll LA, Cadd GG et al. Inhibition of intracellular cAMP-dependent protein kinase using mutant genes of the regulatory type I subunit. J Biol Chem 1987;262:13111–13119.

11 Di Bella DJ, Habibi E, Stickels RR et al. Molecular logic of cellular diversification in the mouse cerebral cortex. Nature 2021;595:554–559.

12 Fu Y, Yang M, Yu H et al. Heterogeneity of glial progenitor cells during the neurogenesis-to-gliogenesis switch in the developing human cerebral cortex. Cell Rep 2021;34:108788.

13 Girskis KM, Stergachis AB, DeGennaro EM et al. Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions. Neuron 2021;109:3239–3251.e7.

14 Govindan S, OberstJabaudon D. In vivo pulse labeling of isochronic cohorts of cells in the central nervous system using FlashTag. Nat Protoc 2018;13:2297–2311.

15 Hebert JM, Fishell G. The genetics of early telencephalon patterning: some assembly required. Nat Rev Neurosci 2008;9:678–685.

16 Hebert JM, Mishina Y, McConnell SK. BMP signaling is required locally to pattern the dorsal telencephalic midline. Neuron 2002;35:1029–1041.

17 Hoch RV, Rubenstein JL, Pleasure S. Genes and signaling events that establish regional patterning of the mammalian forebrain. Semin Cell Dev Biol 2009;20:378–386.

18 Huang X, Ketova T, Fleming JT et al. Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus. Development 2009;136:2535–2543.

19 Huang W, Bhaduri A, Velmeshev D et al. Origins and proliferative states of human oligodendrocyte precursor cells. Cell 2020;182:594–608.e11.

20 Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011;27:513–537.

21 Klein RS, Rubin JB, Gibson HD et al. SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001;128:1971–1981.

22 Komada M, Saitsu H, Kinboshi M et al. Hedgehog signaling is involved in development of the neocortex. Development 2008;135:2717–2727.

23 Kretzschmar M, Doody J, Massague J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 1997;389:618–622.

24 Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 2009;32:149–184.

25 Kuschel S, Ruther U, Theil T. A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Dev Biol 2003;260:484–495.

26 LaMonica BE, Lui JH, Hansen DV et al. Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex. Nat Commun 2013;4:1665.

27 Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol 2020;21:607–632.

28 Lewitus E, Kelava I, Kalinka AT et al. An adaptive threshold in mammalian neocortical evolution. PLoS Biol 2014;12:e1002000.

29 Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science 2010;327:542–545.

30 Li X, Newbern JM, Wu Y et al. MEK is a key regulator of gliogenesis in the developing brain. Neuron 2012;75:1035–1050.

31 Li S, Mattar P, Dixit R et al. RAS/ERK signaling controls proneural genetic programs in cortical development and gliomagenesis. J Neurosci 2014;34:2169–2190.

32 Li X, Liu G, Yang L et al. Decoding cortical glial cell development. Neurosci Bull 2021;37:440–460.

33 Lin Y, Yang J, Shen Z et al. Behavior and lineage progression of neural progenitors in the mammalian cortex. Curr Opin Neurobiol 2021;66:144–157.

34 Liu DD, He JQ, Sinha R et al. Purification and characterization of human neural stem and progenitor cells. Cell 2023;186:1179–1194.e15.

35 Long F, Zhang XM, Karp S et al. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 2001;128:5099–5108.

36 Lui JH, Hansen DV, Kriegstein AR. Development and evolution of the human neocortex. Cell 2011;146:18–36.

37 Lui JH, Nowakowski TJ, Pollen AA et al. Radial glia require PDGFD-PDGFRbeta signalling in human but not mouse neocortex. Nature 2014;515:264–268.

38 Lun MP, Johnson MB, Broadbelt KG et al. Spatially heterogeneous choroid plexus transcriptomes encode positional identity and contribute to regional CSF production. J Neurosci 2015;35:4903–4916.

39 Ma T, Wang C, Wang L et al. Subcortical origins of human and monkey neocortical interneurons. Nat Neurosci 2013;16:1588–1597.

40 Ma L, Du Y, Hui Y et al. Developmental programming and lineage branching of early human telencephalon. EMBO J 2021;40:e107277.

41 Martynoga B, Mateo JL, Zhou B et al. Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence. Genes Dev 2013;27:1769–1786.

42 Micali N, Kim SK, Diaz-Bustamante M et al. Variation of human neural stem cells generating organizer states in vitro before committing to cortical excitatory or inhibitory neuronal fates. Cell Rep 2020;31:107599.

43 Molnar Z, Clowry GJ, Sestan N et al. New insights into the development of the human cerebral cortex. J Anat 2019;235:432–451.

44 Monuki ES, Porter FD, Walsh CA. Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 2001;32:591–604.

45 Nowakowski TJ, Pollen AA, Sandoval-Espinosa C et al. Transformation of the radial glia scaffold demarcates two stages of human cerebral cortex development. Neuron 2016;91:1219–1227.

46 Panchision DM, Pickel JM, Studer L et al. Sequential actions of BMP receptors control neural precursor cell production and fate. Genes Dev 2001;15:2094–2110.

47 Pebworth MP, Ross J, Andrews M et al. Human intermediate progenitor diversity during cortical development. Proc Natl Acad Sci U S A 2021;118.

48 Pelletier J, Thomas G, Volarevic S. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer 2018;18:51–63.

49 Pera EM, Ikeda A, Eivers E et al. Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev 2003;17:3023–3028.

50 Picco N, Garcia-Moreno F, Maini PK et al. Mathematical modeling of cortical neurogenesis reveals that the founder population does not necessarily scale with neurogenic output. Cereb Cortex 2018;28:2540–2550.

51 Pollen AA, Nowakowski TJ, Chen J et al. Molecular identity of human outer radial glia during cortical development. Cell 2015;163:55–67.

52 Rakic P. A century of progress in corticoneurogenesis: from silver impregnation to genetic engineering. Cereb Cortex 2006;16:i3–17.

53 Rao R, Salloum R, Xin M et al. The G protein Galphas acts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis. Cell Cycle 2016;15:1325–1330.

54 Rash BG, Grove EA. Patterning the dorsal telencephalon: a role for sonic hedgehog? J Neurosci 2007;27:11595–11603.

55 Saulnier A, Keruzore M, De Clercq S et al. The doublesex homolog Dmrt5 is required for the development of the caudomedial cerebral cortex in mammals. Cereb Cortex 2013;23:2552–2567.

56 Shi Y, Riese DJ 2nd, Shen J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front Pharmacol 2020;11:574667.

57 Smart IH, Dehay C, Giroud P et al. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb Cortex 2002;12:37–53.

58 Stepien BK, Vaid S, Huttner WB. Length of the neurogenic period-a key determinant for the generation of upperlayer neurons during neocortex development and evolution. Front Cell Dev Biol 2021;9:676911.

59 Sun Y, Hu J, Zhou L et al. Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells. J Cell Sci 2011;124:1867–1877.

60 Telley L, Govindan S, Prados J et al. Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex. Science 2016;351:1443–1446.

61 Theil T, Aydin S, Koch S et al. Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development 2002;129:3045–3054.

62 Tole S, Ragsdale CW, Grove EA. Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes(J). Dev Biol 2000;217:254–265.

63 Trevino AE, Muller F, Andersen J et al. Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution. Cell 2021;184:5053–5069.e23.

64 Ulloa F, Briscoe J. Morphogens and the control of cell proliferation and patterning in the spinal cord. Cell Cycle 2007;6:2640–2649.

65 Vaid S, Camp JG, Hersemann L et al. A novel population of Hopx-dependent basal radial glial cells in the developing mouse neocortex. Development 2018;145:dev169276.

66 Walenkamp AME, Lapa C, Herrmann K et al. CXCR4 ligands: the next big hit? J Nucl Med 2017;58:77S–82S.

67 Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000;100:423–434.

68 Wang F, Flanagan J, Su N et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 2012;14:22–29.

69 Wang C, You Y, Qi D et al. Human and monkey striatal interneurons are derived from the medial ganglionic eminence but not from the adult subventricular zone. J Neurosci 2014a;34:10906–10923.

70 Wang RN, Green J, Wang Z et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis 2014b;1:87–105.

71 Winkler CC, Yabut OR, Fregoso SP et al. The dorsal wave of neocortical oligodendrogenesis begins embryonically and requires multiple sources of Sonic hedgehog. J Neurosci 2018;38:5237–5250.

72 Wyatt AW, Osborne RJ, Stewart H et al. Bone morphogenetic protein 7 (BMP7) mutations are associated with variable ocular, brain, ear, palate, and skeletal anomalies. Hum Mutat 2010;31:781–787.

73 Xiong W, He F, Morikawa Y et al. Hand2 is required in the epithelium for palatogenesis in mice. Dev Biol 2009;330:131–141.

74 Yang X, Li C, Herrera PL et al. Generation of Smad4/Dpc4 conditional knockout mice. Genesis 2002;32:80–81.

75 Yang L, Li Z, Liu G et al. Developmental origins of human cortical oligodendrocytes and astrocytes. Neurosci Bull 2022;38:47–68.

76 Zhang X, Mennicke CV, Xiao G et al. Clonal analysis of gliogenesis in the cerebral cortex reveals stochastic expansion of glia and cell autonomous responses to Egfr dosage. Cells 2020a;9:2662.

77 Zhang X, Xiao G, Johnson C et al. Bulk and mosaic deletions of Egfr reveal regionally defined gliogenesis in the developing mouse forebrain. iScience 2023;26:106242.

78 Zhang Y, Liu G, Guo T et al. Cortical neural stem cell lineage progression is regulated by extrinsic signaling molecule Sonic hedgehog. Cell Rep 2020b;30:4490–4504.e4494.

79 Zhuo L, Theis M, Alvarez-Maya I et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 2001;31:85–94.