Timing in Morphogenesis of the Developing Nervous System: Relation to Genetic Programming and Exogenous Teratogenesis

Main Article Content

Harvey B. Sarnat, MS, MD, FRCPC

Abstract

Timing is essential to morphogenesis of the embryonic and fetal nervous system and intricately associated with onset of expression of developmental genes. Mitotic cell cycles are timed. Teratogenic toxins and other adverse influences are teratogenic in the context of timing by interfering with developmental processes. Each of the 3 axes of the neural tube is associated with two opposing genetic gradients. Many neural malformations can be analyzed pathologically as interference with genetic gradients of one or more of the axes, even if the specific genetic mutation is not yet identified. Examples of cerebral malformations closely associated with defective timing are agenesis of forebrain commissures (anterior and hippocampal commissures form 3 weeks before corpus callosum), neuronogenesis and gliogenesis in disorders of the mTOR signaling pathway (time of expression of postmitotic somatic mutation in relation to the 33 mitotic cycles of neuroepithelium determines extent of lesion of focal cortical dysplasia II or hemimegalencephaly), prosencephalic cleavage and eversion (holoprosencephaly; telencephalic flexure for Sylvian fissure), neuromeric disorders of segmentation of the neural tube (deletion of neuromeres; Chiari I), maturation of individual neurons, synaptogenesis (precocious synaptic circuitry in holoprosencephaly; delayed synapse formation in many genetic/metabolic encephalopathies), myelination (delay in many congenital encephalopathies) and neural crest migrations including craniofacial development (facial dysmorphisms in many genetic syndromes and hypertelorism in some cases of callosal agenesis). Timing of relation of genes in cascade or inhibitory genes acting on others is a key element of normal and abnormal morphogenesis.

Keywords: timing, morphogenesis, development, nervous system, embryo, fetus

Article Details

How to Cite
SARNAT, Harvey B.. Timing in Morphogenesis of the Developing Nervous System: Relation to Genetic Programming and Exogenous Teratogenesis. Medical Research Archives, [S.l.], v. 11, n. 6, june 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3940>. Date accessed: 07 nov. 2024. doi: https://doi.org/10.18103/mra.v11i6.3940.
Section
Research Articles

References

1. Pitsawong W, Padua RAP, Grant T, Hoemberger M, Otten R, Bradshaw N, et al. From primordial clocks to circadian oscillators. Nature 2023;616:183-189.
2. Crane BR, Young MW. Interactive features of proteins composing eukaryotic circadian clocks. Ann Rev Biochem 2014;83:191-219.
3. Takashashi TS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 2017;18:164-179.
4. Lin C, Feng S, DeOliveira CC, Crane BR. Cryptochrome-timeless structure reveals circadian clock timing mechanisms. Nature 2023;617:194-199.
5. Tsang M-J, Cheeseman IM. Alternative CDC20 translational isoforms tune mitotic arrest duration. Nature 2023;617:154-161.
6. Pagán OR. The First Brain. The Neuroscience of Planarians. NY, Oxford: Oxford University Press. 2014.
7. Martin-Zamora FM, Liang Y, Guynes K, Carrillo-Baltodano AM, Davies BE, Donnellan RD, et al. Annelid functional geonomics reveal the origins of bilaterian life cycles. Nature 2023;615:105-110.
8. Sarnat HB, Menkes JH. The new neuroembryology: How to construct a neural tube. J cc
9. Sarnat HB. The new neuroembryology: Molecular genetic classification of central nervous system malformations. J Child Neurol 2000;21:675-687.
10. Sarnat HB, Flores-Sarnat L. Morphogenesis timing of genetically-programmed brain malformations in relation to epilepsy. Progr Brain Res 2014;213:181-198.
11. Sarnat HB. The 2016 Bernard Sachs Lecture: Timing in morphogenesis and genetic gradients during normal development and in malformations of the nervous system. Pediatr Neurol 2018;83:3-13.
12. Mühlebner A, Bongaarts A, Sarnat HB, Scholl T, Aronica E. New insights into a spectrum of developmental malformations related to mTOR dyregulations: Challenges and perspectives. J Anat 2019;235:521-542.
13. Sarnat HB, Blümcke I, Miyata H, Vinters HV. Epilepsy: A Comprehensive Textbook. 3rd ed. Chapter 13: Neuropathology of Developmental Disorders Associated with Epilepsy. Philadelphia: Walters Kluwers. 2023. in press.
14. D’Gama AM, Geng Y, Couto JA, Martin B, Boyle EA, LaCoursière CM, et al. mTOR pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 2015;77:720-725.
15. Caviness VS Jr, Pinto-Lord MC, Evrard P. The development of laminated patterns in the mammalian neocortex. In: Morphogenesis of Pattern Formation. Connelly TG, ed. NY: Raven Press. 1981. pp 103-126.
16. Curatolo P, Specchio N, Aronica E. Advances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy. Lancet Neurol 2022;21(9):843-856.
17. Sarnat HB. Regional differentiation of the human fetal ependyma: immunocytochemical markers. J Neuropathol Exp Neurol 1992;51:58-75.
18. Sarnat HB, Netsky MG. Evolution of the Nervous System. Oxford, NY: Oxford University Press. 1978. pp 324-326.
19. Golden JA. Holoprosencephaly: a defect in brain patterning. J Neuropathol Exp Neurol 1998;57:991-999.
20. Sarnat HB, Flores-Sarnat L. Neuropathological research strategies in holoprosencephaly. J Child Neurol 2001;16:918-931.
21. Kallén B. Early morphogenesis and pattern formation in the central nervous system. In: DeHann (ed). Organogensis. New York: Holt, Rhinehart & Winston, 1965, pp. 107-128.
22. McClure CFW. The segmentation of the primitive vertebrate brain. J Morphol 1980;4:35-56. 103.
23. Lumsden A. The cellular basis of segmentation in the developing hindbrain. Trends Neurosci 1990;13:329-335.
24. Keynes R, Lumsden A. Segmentation and the origin of regional diversity in the vertebrate central nervous system. Neuron 1990;2:1-9.
25. McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68:283-302.
26. Keynes R, Krumlauf R, Hox genes and regionalization of the nervous system. Annu Rev Neurosci 1994;17:109-132.
27. Krumlauf R. Hox genes in vertebrate development. Cell 1994;78 :191-201.
28. Joyner AL. Engrailed, Wnt and Pax genes regulate midbrain-hindbrain development. Trends Genet 1996;12:15-20.
29. Joyner AL. Engrailed, Wnt and Pax genes regulate midbrain-hindbrain development. Trends Genet 1997;124:2923-2934.
30. Carstens MH, Sarnat HB. Neuromeres: The timing and sequence of their appearance and their relationship to brain development. In: Developmental Principles of Head and Neck Anatomy: The Neuromeric Basis of Craniofacial Structure. Carstens MH, ed. Berlin, NY: Springer-Verlag. 2023; in press.
31. Herrick CJ. The morphology of the forebrain in amphibia and reptiles. J Comp Neurol Psychol. 1910;20:413-547.
32. Herrick CJ. The Brain of the Tiger Salamander, Amblystoma tigrinum. Chicago: University of Chicago Press. 1948.
33. Rubenstein JLR. The prosomeric model: a proposal for the organization of the embryonic forebrain. Science 1994; 266:578-580.
34. Puelles l, Rubenstein JLR. Expression patterns of homeobox and other putative regulatory genes in the embryonic mouse forebrain suggest a neuromeric pattern. Trends Neurosci 1993; 16:472-479.
35. Puelles L, Rubenstein JLR. Forebrain gene expression domains and the evolving prosomeric model. Trends Neurosci 2003;26:469-476.
36. Puelles L, Harrison M, Paxinos G, Watson C. A developmental ontology for the mammalian brain based on the prosomeric model. Trends Neurosci 2013;36:570-578.
37. Mai JK, Andressen C, Ashwell KWS. Demarcation of prosencephalic regions by CD15-positive radial glia. Eur J Neurosci 1998;10:756-751.
38. Kuemerle B, Zanjani H, Joyner A, et al. Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J Neurosci 1997;17:7881-7889.
39. McMahon AP, Joyner AL, Bradley A, et al. The midbrain-hindbrain phenotype of Wnt-1−/Wnt-1 mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell 1992;69:581-595.
40. Sarnat HB, Benjamin DR, Kletter GB, Seibert JR, Cheyette SR. Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation of the EN2 gene. Report of 2 cases in early infancy. Pediatr Dev Pathol 2002;5:54-68.
41. Ten Donkelaar HJ, Lammens M, Cruysberg JRM, et al. Development and developmental disorders of the brainstem. In: Ten Donkelaar HJ, Lammens M, Hori A, eds. Clinical Embryology: Development and Developmental Disorders of the Human Central Nervous System. Berlin: Springer-Verlag. 2007
42. Selim LA, Zaki MS, Hussein HA, Saleem SN, Kotoury AS, Issa MY. Developmental abnormalities in mid and hindbrain: a study of 23 Egyptian patients. Egypt J Med Hum Genet 2008;9:215-236.
43. Sarnat HB. Disorders of segmentation of the neural tube: Agenesis of neuromeres. Handb Clin Neurol 2008;87:105-113.
44. Sarnat HB. Embryology and malformation of the forebrain commissures. Handb Clin Neurol 2008;87:67-87.
45. Rakic P, Yakovlev P. Development of the corpus callosum. J Comp Neurol 1968;132:45-72.
46. Loeser JD, Alvord EC Jr. Agenesis of the corpus callosum. Brain 1968;91:553-570.
47. Barr MS, Corbellis MC. The role of the anterior commissure in callosal agenesis. Neuropsychology 2002;16:459-471.
48. Sarnat HB. Transitory and vestigial structures of the developing human nervous system. Pediatr Neurol 2021;123:86-101.
49. Zaki W. Le processus dégénératif au cours du développement du corps calleux. Arch Anat Micr Morphol Exper 1985;74:133-149.
50. Sasaki A, Hirato J, Nakazato Y, Ishida Y. Immunohistochemical study of the early human fetal brain. Acta Neuropathol 1988;76:128-134.
51. Honig LS, Herrmann K, Shatz CJ. Developmental changes revealed by immunohistochemical markers in human cerebral cortex. Cerebr Cortex 1996;6:794-806.
52. Sarnat HB. Clinical Neuropathology Practice Guide 5-2013: Markers of neuronal maturation. Clin Neuropathol 2013:32:340-369.
53. Sarnat HB. Immunocytochemical markers of neuronal maturation in human diagnostic neuropathology. Cell Tiss Res 2015;359:279-294.
54. Sarnat HB. Proteoglycan (keratan sulfate) barrier in developing human forebrain isolates cortical epileptic networks from deep heterotopia, insulates axonal fascicles and explains why axosomatic synapses are inhibitory. J Neuropathol Exp Neurol 2019;78:1147-1159.
55. Allen NJ, Eroglu C. Cell biology of astrocyte-synapse interactions. Neuron 2017;96:697-708.
56. Sarnat HB, Rao VTS. Glial Cell Pathology in Genetic and Epigenetic Disorders of the Central Nervous System. Handb Clin Neurol 2023; in press.
57. Sarnat HB, Flores-Sarnat L, Trevenen CL. Synaptophysin immunoreactivity in the human hippocampus and neocortex from 6 to 41 weeks of gestation. Journal of Neuropathology and Experimental Neurology 2010;69:234-245.
58. Sarnat HB, Auer RN, Flores-Sarnat L. Synaptogenesis in the fetal corpus striatum, globus pallidus and substantia nigra. Correlations with striosomes of Graybiel and dyskinesias in premature infants. Journal of Child Neurology 2013;28:60-69.
59. Sarnat HB, Flores-Sarnat L, Auer RN. Sequence of synaptogenesis in the human fetal and neonatal cerebellar system. Part 1. Guillain-Mollaret triangle (dentato-rubro-olivary-cerebellar circuit. Developmental Neuroscience 2013;35:69-81.
60. Sarnat HB, Flores-Sarnat L, Auer RN. Sequence of synaptogenesis in the human fetal and neonatal cerebellar system. Part 2. Pontine nuclei and cerebellar cortex. Developmental Neuroscience 2013;35:317-325.
61. Sarnat HB, Yu W. Maturation and dysgenesis of the human olfactory bulb. Brain Pathol 2016;26:301-318.
62. Sarnat HB, Flores-Sarnat L. Precocious and delayed neocortical synaptogenesis in fœtal holoprosencephaly. Clinical Neuropathology. 2013;32:255-268.
63. Sarnat HB, Resch L, Flores-Sarnat L, Yu W. Precocious synapses in 13.5-week fetal holoprosencephalic cortex and cyclopean retina. Brain and Development 2014;36:463-471.
64. Yakovlev PI, Lecours A-R. The myelination cycles of regional maturation of the brain. In: Minkowsky A, editor. Regional Development of the Brain in Early Life. Philadelphia: FA Davis, 1967. pp 3-70.
65. Rorke LB, Riggs HE. Myelination in the Brain of the Newborn. Philadelphia, Toronto: Lippincott, 1969.
66. Gilles FH. Myelination in the neonatal brain. Brain Pathol 1976;7:244-8.
67. Kinney HC, Brody BA, Kloman AS, et al. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol 1988;47(3):217-34.
68. Hughes EG, Appel B. The cell biology of CNS myelination. Curr Opin Neurobiol 2016;39:93-100.
69. McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogle JFJ, Hoffmann A, et al. Microglia regulate central nervous system myelin growth and integrity. Nature 2023;613:120-129.
70. Sarnat HB, Hader W, Flores-Sarnat L, Bello-Espinosa L. Synaptic plexi of the U-fibre layer beneath focal cortical dysplasias: role in epileptic networks. Clin Neuropathol 2018;37:262-276.
71. Sarnat HB, Flores-Sarnat L. Synaptogenesis and myelination in the nucleus/tractus solitarius. Potential role in apnoea of prematurity, congenital central hypoventilation and sudden infant death syndrome. J Child Neurol 2016;31:722-732.