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Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITY

Consortium members

SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***

**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben

***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.

PETER PAZMANY CATHOLIC UNIVERSITY

SEMMELWEIS UNIVERSITY

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Peter Pazmany Catholic University Faculty of Information Technology

BEVEZETÉS A FUNKCIONÁLIS NEUROBIOLÓGIÁBA

INTRODUCTION TO

FUNCTIONAL NEUROBIOLOGY

www.itk.ppke.hu

By Imre Kalló

Contributed by: Tamás Freund, Zsolt Liposits, Zoltán Nusser, László Acsády, Szabolcs Káli, József Haller, Zsófia Maglóczky, Nórbert Hájos, Emilia Madarász, György Karmos, Miklós Palkovits, Anita Kamondi, Lóránd Erőss, Róbert

Gábriel, Zoltán Kisvárday

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Stem cells and potential applications

Imre Kalló & Emilia Madarász

Pázmány Péter Catholic University, Faculty of Information Technology

I. Undifferentiated cells during embryogenesis and throughout life II. Proliferation versus differentiation

III. Migration, axonal growth and synapse formation

IV. Potential application of stem cells; from experiments to therapy

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Neurons maintain a complex cellular morphology

Axon

Dendrite

100 μm

s.r.

s.o.

Dendrite (D) s.p.

Cell body

Axon (A) Pyramidal cell

Cerebral cortex

Interneuron Hippocampus

D A

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Two dogma persisted about neurons for a long time

1. Mature neurons do not divide:

2. We have to manage our life with the set of neurons present at early postnatal period:

1984 Notebohm: song-birds

1992 Reinolds és Weiss: rodents, human

Conclusion of these studies:

Nondifferentiated cells with the capability to produce new neurons are present throughout life.

Where are the neurogenic zones?

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Location of proliferating cells (forming a germinative layer) in the neural primordium of human and rat embryos

The neural plate comprises the shoehorn-shaped dorsal thickening of the ectoderm at the rostral end of the early embryo. The neural plate forms the neural tube, which initially remains open at the caudal and rostral ends. The rostral part of the neural tube establishes the primordium of the brain. The neural tube is composed of a single layer of proliferating cells, the primary germinative layer. A second germinative layer appears in later stages of embryonic development under the ventricular wall through-out the entire neuraxis. In the ventral part of the forebrain the subventricular zone is the best explored residence of the stem cells during adulthood. Similar important adult neurogenic zone, the subgranular zone is located beneath the granule cell layer of the hippocampus.

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Location of proliferating cells (forming a germinative layer) in the neural primordium of human and rat embryos

6-day old human embryo

8 –day old human embryo

Rat forebrain

Primary germinative zone Secundary germinative zone E10.5

Adult

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Location of stem cells (with the capability to proliferate) in the adult rat brain

Subventricular zone Subgranular zone

Cerebral cortex Olfactory

bulb

Ventricle

Cerebellum

Brainstem Corpus callosum

Primary migratory pathway

Thalamus

Neurosphere

From a new born mouse forebrain

10μm

Hippocampus

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Cell proliferation and interkinetic migration of the cell nucleus in the primary ventricular zone

+

+

Location of future pial surface

G1 S M Cell-phase

Location of future ventricular surface

Symmetrical mitosis

Asymmetrical mitosis

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Cell proliferation and interkinetic migration of the cell nucleus in the primary ventricular zone

ventricle

Pia - ECM

Radial glia Radial neuro-

epithelial cell

ECM

Neuronal precursor

Lateral induction /

inhibition

symmetric asymmetric mitoses

Notch Hes ErbB2 BLBP

Delta-1 Mash/Ngn1,2 NRG-1 Ref: Halfter W, Dong S, Yip YP, Willem M, Mayer U. A critical function of the pial

basement membrane in cortical histogenesis. J Neurosci. 2002 Jul 15;22(14):6029-40.

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Notch/Delta system

differentiating cell undifferentiating cell In general:

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Signalling pathways activated

DSL – Delta, Serrate, Lag-2 CSL – CBF1, Su(H), Lag-1 NICD – Notch Intracellular Domain TACE/ADAM17 – TNFα Converting Enzyme

A Disintegrin And Metalloprotease

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Lateral inhibition (Drosophila proneuronal cluster)

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Role of bHLH transcription factors during differentiation

Basic helix-loop-helix transcriptional factors

H

bHLH

L H

Pro-neural

Mash 1..., Ngn 1,2, Math 1

Neural

Math 2, NeuroD

Ryoichiro Kageyama and Shigetada Nakanishi; Current Opinion in Genetics & Development 1997, 7:659-665

Neural progenitor Neural precursor Neuron Notch

Delta Notch

ICD RBP-J

Hes1 Hes5

Mash1 Math1 Ngn E2A

NeuroD Math2E2A

Hes1 Hes5

Mash1 Math1 ngn

NeuroD Math2

Neuron- specific genes

Cytoplasm

Nucleus

Groucho

Migration Terminal

differentiation

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Migration of embryonic cells from the primary germinative zone

Radial glia Migrating neuronal

precursors

Neuronal precursors deriving from the primary germinative zone migrate along the processes of radial glial cells

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

The secundary germinative zone derives from the primary one:

Primary germinative layer Secundary germinative layer

prenatal postnatal

Projecting neuron

Small projecting neuron

Local interneuron Astroglial cells

Radial glia

ependyma VZ

SVZ

Projecting neurons are not produced

The neurogenic zones in adulthood are remnants of the SVZ

+ dentate gyrus subgranular zone

(SGZ)

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Migration of cells in adulthood

brain tissue

ependyma

ventricle

The neuronal precursors migrate among the

already differentiated hippocampal neurons The neuronal precursors migrate separated from the already differentiated neurons

Subgranular zone Subventricular zone

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

The antero-posterior axis is defined by the primitive streak and antero-visceral entoderm (AVE)

epiblast

hypoblast

AVE Primitive streak

A testtengely P

AVE Primitív árok

A testtengely P

Nodus

Schönwolf, Colas;

DEVELOPMENTAL DYNAMICS 221:117–145 (2001)

Primitive groove

Body axis Body axis

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

The antero-posterior axis is defined by the primitive streak and antero-visceral entoderma (AVE)

Dorso-ventral axis: Shh / Wnt

A

neural crest

SHH alar

plate

basal plate

roof plate

basal plate SHH, Gli 1,2

B A

P

V D

Shimamura, Rubenstein; 1995

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Cranio-caudal expression pattern of homeobox genes

Hirth et al., (1998).

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Differentiation of rhombomeres

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Differentiation of neuronal populations in the brain

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

The cerebral cortex is built up by cells deriving from different regions of both the primary and secundary germinative layers

E10.5

E10,5 E1

0, 5

E1 0,5

E10,

Adult5 Shuurmans 2004 Alvarez-Buylla 1998

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Developing of neuronal pathways: axonal growth and path finding

Phase-contrast image of growth cone

Electron microscopic image of growth cone

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Burnette et al., 2008 Cell

Developing of neuronal pathways: axonal growth and pathfinding

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

„Pathfinder” processes: directed growth and „forbidden” directions

Timed appearance of guiding molecules and receptors!

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Ideal adherence of the growth cone to the surface of neighboring processes; they form bundles

Molnár Zoltán felvétele

Processes of cortical neurons „guide” the processes of thalamic neurons to the cortex

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Axonal pathfinding in the visual pathway

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

„Fire together – wire together”

Bioelectric activity

[Ca2+]I Release of materials

BDNF

GABA

[Ca2+]I phosphorilation

Protein synthesis Release of signal molecules ECM

Protein synthesis and release

Growth cone Target cell

GABAA GABAB

GDP

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Formation and subsistence of functional neuronal networks is the result of multiple selection

Production of cells: surviving cells are selected from a multitude of cells with great surplus

Migration of cells: cells are selected by permissive, attractive and repulsive adhesive signals

Axonal growth/withdrawal: the axonal sprouting is excessive; sustained axons „are being selected” by the activity they show

Synapse formation/survival: it is possible only among mutually active partners

Selection by the ambience

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Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

For what purpose can the stem cells be used?

Today „only” for scientific/clinical research

Stem cell therapy is still not sufficiently validated for neuronal diseases and currently is not a choice…….

But there are clinical studies with controls!

(Must be free of charge for the patients!!!)

Secernated factors inducing regeneration, and/or reducing inflammation?

Gene-therapy

Clinical trials: LSDs (e.g. Batten-disease)

Future: Great possibilities in stem cell therapy

(32)

Introduction to functional neurobiology: Stem cells

www.itk.ppke.hu

Location of proliferating cells (forming a germinative layer) in the neural primordium of human and rat embryos

6-day old human embryo

8 –day old human embryo

Rat forebrain

Primary germinative zone Secundary germinative zone E10.5

Adult

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