regulation of vertebrate neuron death in …

REGULATION OF VERTEBRATE NEURON DEATH IN DEVELOPMENT AND NEURODEGENERATION:

ROLE OF TRANSCRIPTION

LLOYD A. GREENECOLUMBIA UNIVERSITY

NEW YORK, NY

• BEARD (1889) - LOSS OF NEURONAL POPULATIONS IN FISH (ROHON-BEARD NEURONS)

• COLLIN (1906) - DEATH OF MANY SENSORY AND MOTOR NEURONS IN THE CHICK EMBRYO

MASSIVE LOSS OF NEURONS DURING VERTEBRATE DEVELOPMENT HAS BEEN

LONG KNOWN

0

5,000

10,000

15,000

20,000

25,000

36 38 40 42 44 46 P2 P4

NORMAL

DEVELOPMENTAL STAGE

NEU

RO

N N

UM

BER

IN C

HIC

K IO

N

APPROXIMATELY 50% OF POST-MITOTIC NEURONS DIEDURING NORMAL DEVELOPMENT

Clarke, Rogers & Cowan J. Comp. Neurol. 167: 125 (1976)

R. Burke Cell Tiss Res (2004)

APOPTOTIC NEURONAL DEATH IN DEVELOPING SUBSTANTIA NIGRA

DEATH OF PROLIFERATING VZ CELLS IN E14 MOUSE CEREBRUM

Blaschke et al J Comp Neurol 1998

Tan = BrDU; Purple = ISEL/dying

FROM Barres and Raff, Journal of Cell Biology, Volume 147, Number 6, December 13, 1999 1123-1128

REGULATED DEVELOPMENTAL DEATH OF OLIGODENDROCYTES

0102030405060708090

100

GENERATED 3 DAYS

SURVIVIOLIGOSOLIGO

SURVIVAL

VIKTOR HAMBURGER AND RITA LEVI-MONTALCINI AND THEBEGINNING OF THE NEUROTROPHIC THEORY OF

DEVELOPMENTAL NEURON DEATH IN VERTEBRATES

VICTOR HAMBURGER AND THE NOTION THAT PERIPHERALTARGETS REGULATE NEURONAL CELL DEATH

ELMER BEUKER AND THE EFFECTS OF SARCOMA 180 ON NEURONAL SURVIVAL

LEVI-MONTALCINI AND THE DISCOVERY OF A DIFFUSIBLE SURVIVAL-PROMOTING ACTIVITY

SARCOMA EXTRACT

LEVI-MONTALCINI AND HAMBURGER DISCOVER A SOLUBLE NERVE-GROWTH PROMOTING ACTIVITY (NGF)

IN EXTRACTS OF SARCOMA 180

PURIFIED NGF PROMOTES NEURON SURVIVAL IN VITRO

NGF

NGF PROMOTES SYMPATHETIC & SENSORY NEURON SURVIVAL IN VITRO

-NGF +NGF

EVIDENCE FOR THE ROLE OF GROWTH FACTORS IN REGULATING DEVELOPMENTAL NEURONAL DEATH IN VIVO

1. INJECTION OF NEW BORN MICE WITH NGF ANTIBODIES YIELDS “IMMUNOSYMPATHECTOMY”

MOTHERS AUTOIMMUNIZED AGAINST NGF PRODUCE OFFSPRING WITH MANY FEWER DORSAL ROOT GANGLIONIC NEURONS

2. SUPPLY OF EXOGENOUS NGF BLOCKS DEVELOPMENTAL CELL DEATH

OF SYMPATHETIC NEURONS

EVIDENCE FOR THE ROLE OF GROWTH FACTORS IN REGULATING DEVELOPMENTAL NEURONAL DEATH IN VIVO

MICE NULL FOR NGF OR ITS RECEPTORS SHOW EXCESS NEURONAL DEATH.

Fagin et al. J Neurosci (1996)

0

5,000

10,000

15,000

20,000

25,000

36 38 40 42 44 46 P2 P4

NORMAL

DEVELOPMENTAL STAGE

NEU

RO

N N

UM

BER

IN C

HIC

K IO

N

NORMAL DEVELOPMENTAL NEURONAL DEATH OCCURS ANDIS REGULATED BY TARGET DERIVED TROPHIC FACTORS

Clarke, Rogers & Cowan J. Comp. Neurol. 167: 125 (1976)

ENUCLEATED

125I-NGF

SCG

050

100150200250300350400450

0 8 16 24 32 40 48

CONTRATERALIPSILATERAL

HOURS

CPMIn SCG

RETROGRADE TRANSPORT OF NEUROTROPHINS FROM TARGETS

Ian Hendry & Hans Thoenen

NEURONAL SURVIVAL AS REGULATED BY COMPETITIONFOR TARGET-SUPPLIED TROPHIC FACTOR

ALL TROPHIC SUPPORT DURING DEVELOPMENT IS NOT NECESSARILY TARGET DERIVED - WHAT KEEPS

NEURONS ALIVE BEFORE THEY INTERACT WITH THEIR TARGETS?

AUTOCRINE LOOPS -NEURONS CAN MAKE THEIR OWN NEUROTROPHIC FACTORS (CORTICAL NEURONS; BDNF)

TISSUE EN ROUTE TO TARGET MAY PROVIDE TROPHIC FACTORS (SUCH AS NT3 AND BDNF)

NEUROTROPHINSNGFBDNFNT3NT4/5

EGF FAMILYEGFTGFαNEUREGULINS

FGF FAMILY

INSULIN & IGFs

TGFβ SUPERFAMILYTGFβBMPsGDNFARTEMINNURTURINPERSEPHIN

CYTOKINESCNTFLIFINTERLEUKINS

PDGF

HGF FAMILYHGFMSP

NEUROPEPTIDESPACAPVIP

GROWTH FACTORS THAT CAN MAINTAIN SURVIVAL OF SELECT NEURONAL POPULATIONS

0102030405060708090

100

GENERATED 3 DAYS

SURVIVIOLIGOS

NEUREGULIN, PDGF

FROM Barres and Raff, Journal of Cell Biology, Volume 147, Number 6, December 13, 1999 1123-1128

REGULATED DEVELOPMENTAL DEATH OF OLIGODENDROCYTES

REMOVAL OF NEURONS WITH TRANSIENT FUNCTIONS

WHY DOES CELL DEATH OCCUR IN VERTEBRATE NEURODEVELOPMENT?

ROHON-BEARD CELLS - LOSS IN ZEBRA FISH

Williams et al. Dev Biol (2000)


CREATION OF SEXUALLY DIMORPHIC STRUCTURES

Chung et al. J Neurbiol (2000)

EX-MALES

M & EX-M+ TEST

BSTpr =Principal nucleus of the Bed nucleus of the striatus terminalis

SEXUALLY DIMORPHIC NEURON DEATH IN RAT BSTpr -REGULATION BY TESTOSTERONE

FEMALES

MALES

MALES

FEMALES

POST NATAL DAY


ELIMINATION OF ECTOPIC NEURONS


ELIMINATION OF NEURONS WITH ECTOPIC PROJECTIONS


“SYSTEMS MATCHING: CREATION OF OPTIMAL LEVELS OFINNERVATION BETWEEN INTERCONNECTED GROUPS OF NEURONS AND BETWEEN NEURONS AND THEIR NON-NEURONAL TARGETS” (Buss and Oppenheim Anat Sci Int, 2004)

WHAT HAPPENS IF DEVELOPMENTAL NEURON CELL DEATH IS ABSENT?

IN ABSENCE OF NORMAL DEVELOPMENTAL CELL DEATH MOST EXCESS NEURONS BECOME ATROPHIC:

EXAMPLE OF FACIAL NERVE

White et al. J Neurosci 1998

RETINAL NEURON RESPONSES TO LIGHT CHANGE IN ABSENCE OF NORMAL DEVELOPMENTAL CELL DEATH

GCL=ganglion cell layerINL=inner nuclear layerONL=outer nuclear layerIPL=inner plexiform layer

0

50

100

150

200

250

300

350

400

450

ROD TEST CONE TEST

WTBAX-/- mV

Relativenumber of responding neurons

(Péquignot et al. Dev Dyn 2003


PREVENT OVER-PRODUCTION OF NEUROPROGENITOR CELLS TO GENERATE PROPER SIZED BRAIN

From: Kuida et al Cell:94: 325-337, 1998

EMBRYOGENIC DEFECTS IN A MOUSE LACKING CASPASE-9

WHY DOES CELL DEATH OCCUR IN NEURODEVELOPMENT?

ELIMINATION OF CELLS WITH DAMAGED DNA OR WITHOTHER DEFECTS


“A MEANS OF EVOLUTIONARY CHANGE: ADAPTIVECHANGES IN THE ONTOGENETIC DEATH AND SURVIVALOF CELLS IN REPSPONSE TO GENETIC MUTATION (E.G.THE PRODUCTION OF EXCESS NEURONS COULD BEUSED FOR THE INNERVATION OF NEW TARGETS MADEAVAILABLE BY THE EVOLUTION OF LIMBS)”

(Buss and Oppenheim Anat Sci Int, 2004)

WHAT ARE THE MECHANISMS BY WHICH NEURON SURVIVAL AND DEATH ARE REGULATED DURING

VERTEBRATE DEVELOPMENT?

NGF NT3 BDNF NT4/5

TRKA TRKC TRKB

SPECIFICITY OF NEUROTROPHIN FAMILY RECEPTOR BINDING

TRKANGF

PI3K

AKT

RAS

ERK

SURVIVAL

WORTMANNINLY2942002D/N PI3K

D/N AKT

ACT-AKT

ACT-PI3K

ACT-RASD/N-RAS

PD98059U0126

DEATH IN SOMEPARADIGMS

TRK SIGNALING AND PROMOTION OF NEURON SURVIVAL

BADP- 14-3-3AKT (cytoplasmic)

FRKHP- 14-3-3AKT (cytoplasmic)

EXAMPLES OF HOW AKT PROMOTES SURVIVAL

IAP IAPAKTTRANSCRIPTIONAL

ACTIVATION

BAD

mitochondria DEATH

FRKH

nucleusBim DEATH

MITOCHONDRIA AND APOPTOTIC DEATH

CYTOCHROME C

mitochondrion BCL2BCL2

BAX BIM

BAX

BIM

BAX

BIM

BAX

BIM

APOPTOTIC STIMULI

BAKBAK

EGL1

CED9

CED4

CED3

CASPASE 9 ACTIVATION

APAF1 (APOPTOSOME)

CASPASE 3,6,7 ACTIVATION

0

5

10

15

20

25

30

35

VEHICLE CYCLOHEX ACT-D

% PYKNOTICCELLS IN

CERVICALSPINAL CORD

OF CHICKEMBRYO

DEVELOPMENTAL NEURON CELL DEATH IN VERTEBRATES REQUIRES MACROMOLECULAR SYNTHESIS

Plotted from data in: Yaginuma et al. J Neurosci 1996

TRANSCRIPTIONAL REGULATION OF APOPTOTIC DEATH

APOPTOTIC STIMULI


APAF1


CYTOCHROME C AIF

mitochondrionBCL2BCL2 BAXBIM

BAX

BIM

IAPs

SMAC/DIABLO

P53P63p73

cJun FKH E2F NFKB

AKT BLOCKS DEATH AT MULTIPLE LEVELS OF THE APOPTOTIC MECHANISM

APOPTOTIC STIMULI


APAF1


CYTOCHROME CAIF

mitochondrionBCL2BCL2 BAX

BIM

BAX

BIM

IAPs

SMAC

P53/P63/P73

cJun FKH E2F NFKB FAS

FAS-L

ELEVATE ANTI-APOPTOTIC MOLECULESBCLX-L

BLOCK APOPTOTIC TRANSC. PATHWAYS(FKH PHOSPHORYLATION)

BAD

PHOSPHORYLATE, EXCLUDE PRO-APOPTOTIC BAD

NEUROTROPHIC FACTORS/AKT

Eilers et al. J Neurosci 1998

C-JUN IS PHOSPHORYLATED/ACTIVATED IN NGF-DEPRIVEDNEURONS

+NGF -NGF

-NGF+CEP1347

BLOCKING JNK ACTIVATION BLOCKS NEURON DEATH CAUSED BY NGF DEPRIVATION

GDP

POSH

MLKMLK

PO4 PO4 PO4

JIP

MKK4/7JNK

PO4

JUNBIM

PO4

RAC1

APOPTOTIC STIMULI

GTP

DEATH SIGNALING BY THE JNK PATHWAY IN NEURON DEATH

BIM IS A PRO-APOPTOTIC MEMBER OF THE BCL2 FAMILY

Puma

Whitfield et al Neuron 2001

= d/n Jun

Bim

BIM IS UPREGULATED BY NGF DEPRIVATION, PARTLY VIA THE JNK PATHWAY AND CONTRIBUTES TO NEURON DEATH

JIP

GDP

POSH

MLK

MLK MKK4/7JNK

JUNBIM

RAC1

PROTEASOME

MLKS AND POSH ARE DEGRADED IN VIABLE NEURONS

APOPTOTIC STIMULI

JIPPOSH

MLKMLKMKK4/7

JNK

JUNBIM

RAC1

PROTEASOME

APOPTOTIC STIMULI

GTP

PO4PO4

PO4

PO4

MLKS AND POSH ARE STABILIZED BY A FEEDBACK LOOPMECHANISM IN RESPONSE TO APOPTOTIC STIMULI

JIPGTPPOSH

MLKMLK

PO4 PO4

MKK4/7

PO4

JNK

PO4

JUN

PO4

RAC1

APOPTOTIC STIMULI

PROTEASOME

DEATH SIGNALING BY THE JNK PATHWAY IN NEURON DEATH

BIMBIM

Neuronal PC12 cells

Hr -NGF 0 4 8

JNK

1 2 3

POSH

i ii

iii iv

v vi

JIP AND POSH RELOCALIZE IN RESPONSE TO APOPTOTIC STIMULI

CONTROL DNA DAMAGE

JIP

POSH

CELL CYCLE MOLECULES MEDIATE NEURON CELL DEATH EVOKED BY

LOSS OF TROPHIC SUPPORT

E2FRb

RbCHR MOD

TK

BLOCKED ACTIVATION

GENE REPRESSION

CDK4

CD1

PO4

PO4

TRANS-ACTIVATION

GENE DE-REPRESSION

S-PHASE

E2F C-MYB

E2F REGULATES CELL PROLIFERATION

E2F REGULATES CELL PROLIFERATION & NEURON DEATH

CDK4

CD1

S-PHASE

RbCHR MOD

GENE REPRESSION

PO4

GENE DE-REPRESSION

E2F1 C-MYB

p130CHR MOD

GENE REPRESSION

PO4

GENE DE-REPRESSION

E2F4 C-MYB

APOPTOTIC STIMULI ACTIVATE CDK4/6 IN NEURONS

Antibody

p130

p107

pRb

Con

trol

-NGF

+NGF

C-MYB

C-MYB

p130 IS THE MAJOR E2F PARTER ON CHROMATIN IN NEURONS,IS PHOSPHORYLATED AND LOST WITH NGF DEPRIVATION, RESULTING IN MYB DE-REPRESSION AND UP-REGULATION

0 16 16+F

NGF W/D Hrs

SCG

p130

E2F REGULATES CELL PROLIFERATION & NEURON DEATH

CDK4

CD1

p130CHR MOD

GENE REPRESSION

PO4

GENE DE-REPRESSION

E2F4 C-MYB

A. Neuronal PC12 cells

GFP Bim merge

siBim

siB-myb

siC-myb

siCdk4

siLuc

THE E2F PATHWAY LEADS TO BIM UPREGULATION VIACDK4 AND MYB

E2F4 C-MYB

GENE REPRESSION

PO4

GENE DE-REPRESSION

p130SUVH39

HDAC

BIMC-MYB FOXOC-JUN

PO4

E2F AND NEURON CELL DEATH

APOPTOTIC STIMULI

CD1 CDK4CDK4

CD1

THE CDK4-E2F-p130-MYB-BIM PATHWAY OF NEURON CELL DEATH

E2F4p130

C-MYB

GENE REPRESSION

CDK4

CD1

PO4

GENE DE-REPRESSION

SUVH39

HDAC

BIMC-MYB FOXO

C-JUN

PO4APOPTOTIC STIMULI

TRANSCRIPTIONAL REGULATION OF APOPTOTIC DEATH

APOPTOTIC STIMULI


APAF1


CYTOCHROME C AIF

mitochondrionBCL2BCL2 BAXBIM

BAX

BIM

IAPs

SMAC/DIABLO

P53P63p73

cJun FKH E2F NFKB

• THERE IS MASSIVE DEATH OF NEURONS, NEUROPROGENITORS

AND OLIGODENDROGLIA IN NORMAL VERTEBRATE DEVELOPMENT

• THIS IS LARGELY REGULATED BY ACCESS TO LIMITING SUPPLIES OF EXOGENOUS SURVIVAL-PROMOTING TROPHIC FACTORS

• SURVIVAL IS PROMOTED LARGELY BY ACTIVATION OF AKT AS WELL ASOF ERKS AND INVOLVES BLOCKADE OF DEATH PATHWAYS AT MULTIPLE POINTS

• DEVELOPMENTAL NEURON DEATH IS TRANSCRIPTION DEPENDENT

• INDUCTION OF DEATH INVOLVES MULTIPLE PRO-APOTOTIC SIGNALING PATHWAYS, SOME OF WHICH CONVERGE ON INDUCTION OF BH3-DOMAIN PROTEINS

regulation of vertebrate neuron death in …

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