Abstract
The anterior commissure (AC) is a phylogenetically conserved inter-hemispheric connection found among vertebrates with bilateral symmetry. The AC connects predominantly olfactory areas but many aspects of its development and structure are unknown. To fill this gap, we investigated the embryonic and postnatal development of the AC by tracing axons with DiI and the piggyback transposon multicolor system. With this strategy, we show that axon growth during establishment of the AC follows a strictly regulated timeline of events that include waiting periods (“regressive strategies”) as well as periods of active axon outgrowth (“progressive strategies”). We also provide evidence that these processes may be regulated in the midline via overexpression of chondroitin sulfate proteoglycans. Additionally, we demonstrate that the ipsi- and contralateral innervation of piriform cortex occurs simultaneously. Morphologically, we found that 20% of axons were myelinated by postnatal day (P) 22, in a process that occurred fundamentally around P14. By immunohistochemistry, we described the presence of glial cells and two new subtypes of neurons: one expressing a calretinin (CR)−/MAP2+ phenotype, distributed homogeneously inside the AC; and the other expressing a CR+/MAP2+ phenotype that lies beneath the bed nucleus of the stria terminalis. Our results are consistent with the notion that the AC follows a strictly regulated program during the embryonic and postnatal development similarly to other distal targeting axonal tracts.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abudureyimu S et al (2018) Essential role of Linx/Islr2 in the development of the forebrain anterior. Commissure Sci Rep 8:7292. https://doi.org/10.1038/s41598-018-24064-0
Adler CM, Holland SK, Schmithorst V, Wilke M, Weiss KL, Pan H, Strakowski SM (2004) Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study. Bipolar Disord 6:197–203. https://doi.org/10.1111/j.1399-5618.2004.00108.x
Andrews W et al (2006) Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development 133:2243–2252. https://doi.org/10.1242/dev.02379
Brodal A (1948) The origin of the fibers of the anterior commissure in the rat; experimental studies. J Comp Neurol 88:157–205
Brouns MR et al (2000) The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development. Development 127:4891–4903
Brunjes PC (2013) The mouse olfactory peduncle. 2. The anterior limb of the anterior commissure. Front Neuroanat 6:51. https://doi.org/10.3389/fnana.2012.00051
Calloni SF et al (2017) Compound heterozygous variants in ROBO1 cause a neurodevelopmental disorder with absence of transverse pontine fibers and thinning of the anterior commissure and corpus. Callosum Pediatr Neurol 70:70–74. https://doi.org/10.1016/j.pediatrneurol.2017.01.018
Carney RS et al (2006) Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system. J Neurosci 26:11562–11574. https://doi.org/10.1523/JNEUROSCI.3092-06.2006
Chebat DR, Boire D, Ptito M (2006) Development of the commissure of the superior colliculus in the hamster. J Comp Neurol 494:887–902. https://doi.org/10.1002/cne.20856
Chedotal A (2014) Development and plasticity of commissural circuits: from locomotion to brain repair. Trends Neurosci 37:551–562. https://doi.org/10.1016/j.tins.2014.08.009
Chen L et al (2007) Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. J Neurosci 27:3884–3893. https://doi.org/10.1523/JNEUROSCI.3509-06.2007
Collins LN, Hill DL, Brunjes PC (2018) Myelination of the developing lateral olfactory tract and anterior commissure. J Comp Neurol https://doi.org/10.1002/cne.24452
Conway CD, Howe KM, Nettleton NK, Price DJ, Mason JO, Pratt T (2011) Heparan sulfate sugar modifications mediate the functions of slits and other factors needed for mouse forebrain commissure development. J Neurosci 31:1955–1970. https://doi.org/10.1523/JNEUROSCI.2579-10.2011
De Carlos JA, O’Leary DD (1992) Growth and targeting of subplate axons and establishment of major cortical pathways. J Neurosci 12:1194–1211
Deuel TA, Liu JS, Corbo JC, Yoo SY, Rorke-Adams LB, Walsh CA (2006) Genetic interactions between doublecortin and doublecortin-like kinase in neuronal migration and axon outgrowth. Neuron 49:41–53. https://doi.org/10.1016/j.neuron.2005.10.038
Dickson BJ (2002) Molecular mechanisms of axon guidance. Science 298:1959–1964. https://doi.org/10.1126/science.1072165
Dodero L, Damiano M, Galbusera A, Bifone A, Tsaftsaris SA, Scattoni ML, Gozzi A (2013) Neuroimaging evidence of major morpho-anatomical and functional abnormalities in the BTBR T + TF/J mouse model of autism. PLoS One 8:e76655. https://doi.org/10.1371/journal.pone.0076655
Falk J et al (2005) Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 48:63–75. https://doi.org/10.1016/j.neuron.2005.08.033
Fernaud-Espinosa I, Nieto-Sampedro M, Bovolenta P (1996) Developmental distribution of glycosaminoglycans in embryonic rat brain: relationship to axonal tract formation. J Neurobiol 30:410–424. https://doi.org/10.1002/(SICI)1097-4695(199607)30:3%3C410::AID-NEU9%3E3.0.CO;2-7
Figueres-Onate M, Garcia-Marques J, Lopez-Mascaraque L (2016) UbC-StarTrack, a clonal method to target the entire progeny of individual progenitors. Sci Rep 6:33896. https://doi.org/10.1038/srep33896
Fitzpatrick KA, Imig TJ (1980) Auditory cortico-cortical connections in the owl monkey. J Comp Neurol 192:589–610. https://doi.org/10.1002/cne.901920314
Garcia-Marques J, Lopez-Mascaraque L (2013) Clonal identity determines astrocyte cortical heterogeneity. Cereb Cortex 23:1463–1472. https://doi.org/10.1093/cercor/bhs134
Garcia-Moreno F, Lopez-Mascaraque L, de Carlos JA (2008) Early telencephalic migration topographically converging in the olfactory cortex. Cereb Cortex 18:1239–1252. https://doi.org/10.1093/cercor/bhm154
Garcia-Moreno F, Vasistha NA, Begbie J, Molnar Z (2014) CLoNe is a new method to target single progenitors and study their progeny in mouse and chick. Development 141:1589–1598. https://doi.org/10.1242/dev.105254
Gross CG, Bender DB, Mishkin M (1977) Contributions of the corpus callosum and the anterior commissure to visual activation of inferior temporal neurons. Brain Res 131:227–239
Gurdjian ES (1925) Olfactory connections in the albino rat, with special reference to the stria medullaris and the anterior commissure. J Comp Neurol 38:36. https://doi.org/10.1002/cne.900380202
Haberly LB, Price JL (1978a) Association and commissural fiber systems of the olfactory cortex of the rat. J Comp Neurol 178:711–740. https://doi.org/10.1002/cne.901780408
Haberly LB, Price JL (1978b) Association and commissural fiber systems of the olfactory cortex of the rat. II. Systems originating in the olfactory peduncle. J Comp Neurol 181:781–807. https://doi.org/10.1002/cne.901810407
Henkemeyer M, Orioli D, Henderson JT, Saxton TM, Roder J, Pawson T, Klein R (1996) Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 86:35–46
Holt CE, Dickson BJ (2005) Sugar codes for axons? Neuron 46:169–172. https://doi.org/10.1016/j.neuron.2005.03.021
Horel JA, Stelzner DJ (1981) Neocortical projections of the rat anterior commissure. Brain Res 220:1–12
Hua ZL, Jeon S, Caterina MJ, Nathans J (2014) Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system. Proc Natl Acad Sci USA 111:E3005–E3014. https://doi.org/10.1073/pnas.1406399111
Huilgol D, Tole S (2016) Cell migration in the developing rodent olfactory system. Cell Mol Life Sci 73:2467–2490. https://doi.org/10.1007/s00018-016-2172-7
Hulshoff Pol HE, Schnack HG, Mandl RC, Cahn W, Collins DL, Evans AC, Kahn RS (2004) Focal white matter density changes in schizophrenia: reduced inter hemispheric connectivity. Neuroimage 21:27–35
Inatani M, Irie F, Plump AS, Tessier-Lavigne M, Yamaguchi Y (2003) Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 302:1044–1046. https://doi.org/10.1126/science.1090497
Iozzo RV (1998) Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67:609–652. https://doi.org/10.1146/annurev.biochem.67.1.609
Jouandet ML (1982) Neocortical and basal telencephalic origins of the anterior commissure of the cat. Neuroscience 7:1731–1752
Jouandet ML, Gazzaniga MS (1979) Cortical field of origin of the anterior commissure of the rhesus monkey. Exp Neurol 66:381–397
Jouandet ML, Hartenstein V (1983) Basal telencephalic origins of the anterior commissure of the rat. Exp Brain Res 50:183–192
Kallen B (1954) The embryology of the telencephalic fibre systems in the mouse. J Embryol Exp Morphol 2:87–100
Kantor DB et al (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975. https://doi.org/10.1016/j.neuron.2004.12.002
Kaprielian Z, Imondi R, Runko E (2000) Axon guidance at the midline of the developing. CNS Anat Rec 261:176–197
Kassai H, Terashima T, Fukaya M, Nakao K, Sakahara M, Watanabe M, Aiba A (2008) Rac1 in cortical projection neurons is selectively required for midline crossing of commissural axonal formation. Eur J Neurosci 28:257–267. https://doi.org/10.1111/j.1460-9568.2008.06343.x
Kikinis Z et al (2015) Anterior commissural white matter fiber abnormalities in first-episode psychosis: a tractography study. Schizophr Res 162:29–34. https://doi.org/10.1016/j.schres.2015.01.037
Klambt C, Goodman CS (1991) Role of the midline glia and neurons in the formation of the axon commissures in the central nervous system of the Drosophila embryo. Ann N Y Acad Sci 633:142–159
Klingler E et al (2015) The cytoskeleton-associated protein SCHIP1 is involved in axon guidance, and is required for piriform cortex and anterior commissure development. Development 142:2026–2036 https://doi.org/10.1242/dev.119248
Koizumi H, Tanaka T, Gleeson JG (2006) Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration. Neuron 49:55–66. https://doi.org/10.1016/j.neuron.2005.10.040
Kudo C, Ajioka I, Hirata Y, Nakajima K (2005) Expression profiles of EphA3 at both the RNA and protein level in the developing mammalian forebrain. J Comp Neurol 487:255–269. https://doi.org/10.1002/cne.20551
Kullander K, Mather NK, Diella F, Dottori M, Boyd AW, Klein R (2001) Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29:73–84
Larriva-Sahd J, Condes Lara M, Martinez-Cabrera G, Varela-Echavarria A (2002) Histological and ultrastructural characterization of interfascicular neurons in the rat anterior commissure. Brain Res 931:81–91
Legland D, Arganda-Carreras I, Andrey P (2016) MorphoLibJ: integrated library and plugins for mathematical morphology with ImageJ. Bioinformatics 32:3532–3534. https://doi.org/10.1093/bioinformatics/btw413
Lent R, Guimaraes RZ (1990) Development of interhemispheric connections through the anterior commissure in hamsters. Braz J Med Biol Res 23:671–675
Lent R, Guimaraes RZ (1991) Development of paleocortical projections through the anterior commissure of hamsters adopts progressive, not regressive strategies. J Neurobiol 22:475–498. https://doi.org/10.1002/neu.480220505
Lent R, Hedin-Pereira C, Menezes JR, Jhaveri S (1990) Neurogenesis and development of callosal and intracortical connections in the hamster. Neuroscience 38:21–37
Lent R, Uziel D, Baudrimont M, Fallet C (2005) Cellular and molecular tunnels surrounding the forebrain commissures of human fetuses. J Comp Neurol 483:375–382. https://doi.org/10.1002/cne.20427
Lustig M, Erskine L, Mason CA, Grumet M, Sakurai T (2001) Nr-CAM expression in the developing mouse nervous system: ventral midline structures, specific fiber tracts, and neuropilar regions. J Comp Neurol 434:13–28
Maeda N (2015) Proteoglycans and neuronal migration in the cerebral cortex during development and disease. Front Neurosci 9:98. https://doi.org/10.3389/fnins.2015.00098
Maeda N, Ishii M, Nishimura K, Kamimura K (2011) Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem Res 36:1228–1240. https://doi.org/10.1007/s11064-010-0324-y
Margolis RU, Margolis RK (1997) Chondroitin sulfate proteoglycans as mediators of axon growth and pathfinding. Cell Tissue Res 290:343–348
Martin-Lopez E, Garcia-Marques J, Nunez-Llaves R, Lopez-Mascaraque L (2013) Clonal astrocytic response to cortical injury. PLoS One 8:e74039. https://doi.org/10.1371/journal.pone.0074039
Martin-Lopez E, Ishiguro K, Greer CA (2017) The laminar organization of piriform cortex follows a selective developmental and migratory program established by cell lineage. Cereb Cortex. https://doi.org/10.1093/cercor/bhx291
Misaki K, Kikkawa S, Terashima T (2004) Reelin-expressing neurons in the anterior commissure and corpus callosum of the rat. Brain Res Dev Brain Res 148:89–96
Munakata H, Nakamura Y, Matsumoto-Miyai K, Itoh K, Yamasaki H, Shiosaka S (2003) Distribution and densitometry mapping of L1-CAM immunoreactivity in the adult mouse brain—light microscopic observation. BMC Neurosci 4:7
Nawabi H, Castellani V (2011) Axonal commissures in the central nervous system: how to cross the midline? Cell Mol Life Sci 68:2539–2553. https://doi.org/10.1007/s00018-011-0691-9
Pires-Neto MA, Lent R (1991) Pioneer axons in the anterior commissure of hamster embryos. Braz J Med Biol Res 24:1067–1070
Pires-Neto MA, Braga-De-Souza S, Lent R (1998) Molecular tunnels and boundaries for growing axons in the anterior commissure of hamster embryos. J Comp Neurol 399:176–188
Popp S, Andersen JS, Maurel P, Margolis RU (2003) Localization of aggrecan and versican in the developing rat central nervous system. Dev Dyn 227:143–149. https://doi.org/10.1002/dvdy.10282
Raasakka A, Kursula P (2014) The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function. Neurosci Bull 30:956–966. https://doi.org/10.1007/s12264-013-1437-5
Ramon y Cajal S (1901) Estudios sobre la corteza cerebral humana IV. Estructura de la corteza cerebral olfativa del hombre y mamíferos. Trabajos del Laboratorio de Investigaciones Biológicas de la Universidad de Madrid 1:1–140
Raponi E, Agenes F, Delphin C, Assard N, Baudier J, Legraverend C, Deloulme JC (2007) S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia 55:165–177. https://doi.org/10.1002/glia.20445
Robichaux MA, Chenaux G, Ho HY, Soskis MJ, Greenberg ME, Henkemeyer M, Cowan CW (2016) EphB1 and EphB2 intracellular domains regulate the formation of the corpus callosum and anterior commissure. Dev Neurobiol 76:405–420. https://doi.org/10.1002/dneu.22323
Sahay A, Molliver ME, Ginty DD, Kolodkin AL (2003) Semaphorin 3F is critical for development of limbic system circuitry and is required in neurons for selective CNS axon guidance events. J Neurosci 23:6671–6680
Sarma AA, Richard MB, Greer CA (2011) Developmental dynamics of piriform cortex. Cereb Cortex 21:1231–1245. https://doi.org/10.1093/cercor/bhq199
Saxena K et al (2012) A preliminary investigation of corpus callosum and anterior commissure aberrations in aggressive youth with bipolar disorders. J Child Adolesc Psychopharmacol 22:112–119. https://doi.org/10.1089/cap.2011.0063
Schambra UB, Lauder JM, Silver J (1992) Atlas of the prenatal mouse brain, 1st edn. Academic Press, San Diego
Schmalfeldt M, Bandtlow CE, Dours-Zimmermann MT, Winterhalter KH, Zimmermann DR (2000) Brain derived versican V2 is a potent inhibitor of axonal growth. J Cell Sci 113(Pt 5):807–816
Schneider S, Gulacsi A, Hatten ME (2011) Lrp12/Mig13a reveals changing patterns of preplate neuronal polarity during corticogenesis that are absent in reeler mutant mice. Cereb Cortex 21:134–144. https://doi.org/10.1093/cercor/bhq070
Shang F, Ashwell KW, Marotte LR, Waite PM (1997) Development of commissural neurons in the wallaby (Macropus eugenii). J Comp Neurol 387:507–523
Shen Y (2014) Traffic lights for axon growth: proteoglycans and their neuronal receptors. Neural Regen Res 9:356–361. https://doi.org/10.4103/1673-5374.128236
Shen Y, Mani S, Donovan SL, Schwob JE, Meiri KF (2002) Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J Neurosci 22:239–247
Silver J, Lorenz SE, Wahlsten D, Coughlin J (1982) Axonal guidance during development of the great cerebral commissures: descriptive and experimental studies, in vivo, on the role of preformed glial pathways. J Comp Neurol 210:10–29. https://doi.org/10.1002/cne.902100103
Snyder JM, Washington IM, Birkland T, Chang MY, Frevert CW (2015) Correlation of versican expression, accumulation, and degradation during embryonic development by quantitative immunohistochemistry. J Histochem Cytochem 63:952–967. https://doi.org/10.1369/0022155415610383
Sturrock RR (1974a) Histogenesis of the anterior limb of the anterior commissure of the mouse brain. 3. An electron microscopic study of gliogenesis. J Anat 117:37–53
Sturrock RR (1974b) Histogenesis of the anterior limb of the anterior commissure of the mouse brain. I. A quantitative study of changes in the glial population with age. J Anat 117:17–25
Sturrock RR (1975) A quantitative electron microscopic study of myelination in the anterior limb of the anterior commissure of the mouse brain. J Anat 119:67–75
Sturrock RR (1976) Development of the mouse anterior commissure. Part I. A comparison of myelination in the anterior and posterior limbs of the anterior commissure of the mouse brain. Zent Vet C 5:54–67
Sturrock RR (1977) Neurons in the mouse anterior commissure. A light microscopic, electron microscopic and autoradiographic study. J Anat 123:751–762
Suarez R, Gobius I, Richards LJ (2014) Evolution and development of interhemispheric connections in the vertebrate forebrain. Front Hum Neurosci 8:497. https://doi.org/10.3389/fnhum.2014.00497
Suto F et al (2005) Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 25:3628–3637. https://doi.org/10.1523/JNEUROSCI.4480-04.2005
Tissir F, Bar I, Jossin Y, De Backer O, Goffinet AM (2005) Protocadherin Celsr3 is crucial in axonal tract development. Nat Neurosci 8:451–457. https://doi.org/10.1038/nn1428
Tole S, Gutin G, Bhatnagar L, Remedios R, Hebert JM (2006) Development of midline cell types and commissural axon tracts requires Fgfr1 in the cerebrum. Dev Biol 289:141–151. https://doi.org/10.1016/j.ydbio.2005.10.020
Treloar HB, Purcell AL, Greer CA (1999) Glomerular formation in the developing rat olfactory bulb. J Comp Neurol 413:289–304
Wahlsten D (1981) Prenatal schedule of appearance of mouse brain commissures. Brain Res 227:461–473
Wang Y, Thekdi N, Smallwood PM, Macke JP, Nathans J (2002) Frizzled-3 is required for the development of major fiber tracts in the rostral. CNS J Neurosci 22:8563–8573
Wang B et al (2017) The autophagy-inducing kinases, ULK1 and ULK2, regulate axon guidance in the developing mouse forebrain via a noncanonical pathway. Autophagy. https://doi.org/10.1080/15548627.2017.1386820
Wise SP, Jones EG (1976) The organization and postnatal development of the commissural projection of the rat somatic sensory cortex. J Comp Neurol 168:313–343. https://doi.org/10.1002/cne.901680302
Wu Y et al (2004) Versican V1 isoform induces neuronal differentiation and promotes neurite outgrowth. Mol Biol Cell 15:2093–2104. https://doi.org/10.1091/mbc.E03-09-0667
Yamaguchi J et al (2018) Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis. Autophagy 14:764–777. https://doi.org/10.1080/15548627.2017.1314897
Zhang J et al (2005) Magnetic resonance diffusion tensor microimaging reveals a role for Bcl-x in brain development and homeostasis. J Neurosci 25:1881–1888. https://doi.org/10.1523/JNEUROSCI.4129-04.2005
Zhou L et al (2008) Early forebrain wiring: genetic dissection using conditional Celsr3 mutant mice. Science 320:946–949. https://doi.org/10.1126/science.1155244
Acknowledgements
We thank Christine Kaliszewski for technical assistance with EM, Jaime Grutzendler for the CNPase antibody, and the very helpful discussions with all members of the Greer Lab.
Funding
Supported in part by NIH NIDCD DC013791, DC015438, and DC012441 to CAG.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All animal procedures were approved by Yale University Animal Care and Use Committee.
Informed consent
This manuscript has been approved by all co-authors and agreed with the submission of the manuscript to Brain Structure and Function.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Martin-Lopez, E., Meller, S.J. & Greer, C.A. Development of piriform cortex interhemispheric connections via the anterior commissure: progressive and regressive strategies. Brain Struct Funct 223, 4067–4085 (2018). https://doi.org/10.1007/s00429-018-1741-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-018-1741-y