CNS Developmental. Anke van Eekelen, PhD. Telethon Institute for Child Health Research

Transcription

1 CNS Developmental Anke van Eekelen, PhD Telethon Institute for Child Health Research (Some slides are modified versions of Prof. Alan Harvey s Neuroscience lecture at ANHB and Dr. Joanne Britto s Dev Neuroscience lecture from 2003)

2 Central Nervous System Lateral view of the ventricles of the brain Dorsal view of the spinal cord

3 The brain is an astonishingly complex structure. However not only is it an amazing structure it is also, to a large degree, self assembling. When development goes wrong it causes great problems as, unlike for example cardiac problems, it does not always lead to death About 1.3% of total births have some neural abnormality

4 Comparative neurology olfactory bulb forebrain pituitary optic lobe cerebellum CODFISH olfactory bulb cerebral cortex cerebellum HORSE forebrain olfactory bulb optic lobe cerebellum FROG cerebral hemisphere superior and inferior colliculi forebrain optic lobe cerebellum olfactory bulb cerebellum HUMAN olfactory bulb forebrain olfactory bulb optic lobe cerebellum ALLIGATOR GOOSE The degree of complexity of the brain in the different vertebrate species reflects its evolution. The basic subdivisions of the forebrain, midbrain and hindbrain are seen in all vertebrates and during evolution the most striking changes have taken place in the rostral part of the forebrain, which gives rise to the olfactory bulb and the telencephalon.

5 Development of the CNS Formation of major brain divisions via Flexures and swellings of neural tube

6 Prosencephalon Forebrain cerebral hemispheres (cerebral cortex, basal ganglia, lateral ventricles etc) - Telencephalon Diencephalon Thalamus, hypothalamus, epithalamus Mesencephalon - (cephalic flexure) Midbrain Rhombencephalon (pontine and cervical flexures) Metencephalon pons, cerebellum Myelencephalon - medulla Spinal cord

7 More specifically: 1- Specification of neural tissue 2- Origin, birth and migration of cells 3- Acquisition of cell phenotype 4- Formation of correct connections

8 1- Specification of neural tissue & neural tube formation

9 Frog blastula Gastrulation stage Neural default model of induction Ectoderm (animal cap) Ventral Dorsal Meso Meso Mesoderm (marginal zone) Marginal zone Endoderm (vegetal region) Endoderm Organizer (Nieuwkoop centre) BMPs ( ectod diff/ neuroectod diff) BMP antagonists (chordin, follistatin, noggin) Weinstein and Hemmati-Brivanlou Curr. Opin. Neurobiol (1997) 7:7-12

10 Formation of neural plate, neural groove and neural tube days

11 Human neural tube closure Anterior neuropore 22 days 23 days Normal Anencephaly Spina bifida Dorsal and transverse sections Anterior and Posterior neuropores are open to amniotic fluid. Neural tube closure in mammals us initiated at several places along the anterior-posterior axis. Different neural tube defects are caused when various parts of the neural tube fail to close. Failure to close the human posterior neural tube at day 27 results in spina bifida. Failure to close the anterior neural tube results in a lethal condition, anencephaly. In this condition, the forebrain remains in contact with the amniotic fluid and subsequently degenerates.

12 Anterior neuropore 23 days Normal Anencephaly Spina bifida s ores

13 Neural crest cells and peripheral NS

14 2- Origin, birth and migration of CNS-cells

15 Neuroepithelial cells bounce up and down

16 Cell migration and radial glia

17 3- Acquisition of cell phenotype in CNS

18 Signalling centres Isthmus - midbrain/hindbrain boundary chick mouse Shh Wnt1 Fgf8 Dopaminergic neurons Serotonergic neurons Wurst and Bally-Cuif Nature Rev Neurosci : What is a morphogen? Diffusible factor that carries information relating to the position in the embryo, and thus determines the fate of cells perceiving this information Secreted factors Shh - Sonic hedgehog, Fgf8 - Fibroblast growth factor 8 vs Transcription factors Wnt1, En - Engrailed, Pax 2/5/8

19 Neuronal differentiation Specification of neuronal identity by SHH SHH expression Neuronal induction V1, V2, V3 interneruons; MN motor neurons; FP floor plate; N notochord SHH is a morphogen SHH can induce naive neuroepithelial cells to differentiate SHH is secreted from the notochord and decreases in concentration towards the dorsal neural tube Concentration specific induction of floor plate, motorneurons and interneurons Briscoe and Ericson Sem Cell Dev Biol (1999) 10:353

20 Patterning Hindbrain segmentation (AP Axis) Identity is conferred onto each rhombomere by the expression of different transcription factors Hox gene family of proteins Sek gene family of proteins Rhombomere 1 (metencephalon) is not specified by these transcription factors... Lateral view of a 48 h chick embryo Lumsden and Krumlauf Science 1996:

21 Patterning Hindbrain segmentation (AP Axis) Why form segments? Hox genes encode positional value along the AP axis This forms developmental compartments that provide a way of allocating blocks of cells with distinct properties Restriction of neuron axonal projectories (cranial nerves V, VII, VIII, IX) Confer rhombomere-specific identities to motor neurons Flatmount of neural tube Lumsden and Krumlauf Science 1996:

22 4- Formation of correct connections

23 Rodent brain

24 Human CNS

25 Synaptogenesis and Synaptic Pruning Adolescent brain maturation Human Brain Development; Thompson & Nelson 2001