Human brain malformations and their lessons for neuronal migration annual review of neuroscience difference between hypoxia and anoxia

▪ abstractthe developmental steps required to build a brain have been recognized as a distinctive sequence since the turn of the twentieth century. As marking tools for experimental embryology emerged, the cellular events of cortical histogenesis have been intensively scrutinized. On this rich backdrop, molecular genetics provides the opportunity to play out the molecular programs that orchestrate these cellular events. Genetic studies of human brain malformation have proven a surprising source for finding the molecules that regulate CNS neuronal migration. These studies also serve to relate the significance of genes first identified in murine species to the more complex human brain.


The known genetic repertoire that is special to neuronal migration in brain has rapidly expanded over the past five years, making this an appropriate time to take stock of the emerging picture.Difference between hypoxia and anoxia we do this from the perspective of human brain malformation syndromes, noting both what is now known of their genetic bases and what remains to be discovered. Keywords

TABLE 1summary of genes affecting neuronal migration in the central nervous system

Mutation phenotype

Migration molecule a

Gene

Murine

Human

References

Platelet activating factor

LIS1

Lis1−/+ animals with

Miller dieker syndrome

Reiner et al 1993

Acetylhydrolase 1b1

Neuronal migration

(MDS)

LoNigro et al 1997

(pafah1b1)

Delay

Lissencephaly (ILS) b

Hirotsune et al 1998

(signaling/tubulin

(class lisa1-4)

Ross et al 2001

Cytoskeletal dynamics)

LIS with cerebellar

Hypoplasia (LCH)

(class lcha)

Doublecortin (dbcn)

DCX/XLIS

Double cortex (DC) or

Gleeson et al 1998

difference between hypoxia and anoxia

(microtubule associated

(SBH) subcortical

Des portes et al 1998

Protein-cytoskeletal

Band heterotopia

Pilz et al 1998

Dynamics)

X-linked LIS (XLIS)

Ross et al 2001

(class lisb1-4)

LCH (class lcha)

Reelin [extracellular

RELN

Reeler: inverted cortex

LCH (class lchb)

Caviness 1977

Matrix (ECM) molecule]

With layer 5 neurons

D’arcangelo et al 1995

Superficial, failure of

Sheppard et al 1997

Preplate to split

Hong et al 2000

Disabled (docking protein

DAB

Scrambler/yotari

LCH? (predicted, based

Sheldon et al 1997

For cabl tyrosine kinase,

(phenotype identical to

On similarity of reeler and

Ware et al 1997

Intracellular signaling)

Reeler)

Scrambler mice)

VLDLR, apoer2

VLDLR

Knockouts with reeler-

Heisberger et al 1999

(lipoprotein receptors that

difference between hypoxia and anoxia

ApoER2

Like cortex

Trommsdorff et al 1999

Also bind reelin)

D’arcangelo et al 1999

Cdk5 (neurofilament

CDK5

Knockout with reeler-

Gilmore et al 1998

Phosphorylation)

Like cortex

P35 (activating subunit of

P35

Knockout similar but

Chae et al 1997

Cdk5)

Less severe than

Kwon tsai 1998

Cdk5 −/− nulls

Peroxisomal proteins

PEX2

Deficient mice display

Zellweger syndrome

Faust hatten 1997

Pxr1

Heterotopia similar to

Baes et al 1997

Zellweger patients

Filamin-1 (actin

FLN1

Bilateral periventricular

Fox et al 1998

Crosslinking phospoprotein)

Nodular heterotopia

(BPNH), neurons fail to

Leave the VZ

Fukutin (putative ECM

FCMD

Fukuyama congenital

Kobayashi et al 1998

Protein)

Muscular dystrophy

(FCMD)-cobblestone

Complex type II LIS

Myopathy

Anosmin-1 (ECM protein)

difference between hypoxia and anoxia

KAL1

Kallmann syndrome

Hardelin et al 1992

Soussi-vanicostas et al 1998

Astrotactin 1 (neuronal

ASTN1

Nulls with neuronal

Adams et al 2001

Surface molecule)

Migration delay in

Cerebellum and cortex

TABLE 2summary of genes affecting neurite outgrowth in central nervous system

Mutation phenotype

Nutrition outgrowth a

Gene

Murine

Human

References

Mammalian enabled (mena)

MENA

Marked axonal

Lanier et al 1999

(actin reorganization/adhesion)

Projection defects in −/−

Exacerbated by loss of

Profilin 1

Ableson (phosphorylates

CABL

Nulls are early postnatal

Zukerberg et al 2000

Cdk5)

Lethals

Abl related gene (tyrosine

ARG

Enriched in CNS,

Koleske et al 1998

Kinase regulates actin

Colocalizes with cabl/F

Cytoskeleton)

Actin

Neural tube defect in

difference between hypoxia and anoxia

Double abl/arg nulls

Profilin (binds mena and

Profilin I

B chickadee mutation in

Suetsugu et al 1998

Regulates actin

Profilin II

Drosophila identical to

Wills et al 1999

Polymerization)

Growth cone arrest of

CAbl nulls

Slit (ligand of robo, repels

Slit 1

Axon outgrowth from

Rothberg et al 1990

Midline axons)

Slit 2

Retinal explants

Ringstedt et al 2000

Inhibited by slit 2

Transfected cells

Roundabout (repulsive axon

Robo

BSlit/robo interactions

Brose et al 1999

Guidance receptor)

First identified in flies;

Bashaw et al 2000

Drosophila. Slit repels

Spinal motor axons in

Culture

Cdk5 (modulates actin

CDK5

P35/cdk5 localized to

Nikolic et al 1996

Dynamics via rac gtpase

Growth cones; mutant

Nikolic et al 1998

And pak1)

Forms inhibit neurites

difference between hypoxia and anoxia

P35 (activating subunit of

P35

P35 nulls reveal callosal

Kwon et al 1999

Cdk5)

Axon guidance defects

Reelin (ECM protein)

RELN

Neurite outgrowth and

LCH with pachygyria,

Borrell et al 1999a, b

Neuronal synaptogenesis

Marked cerebellar

Hong et al 2000

Defects

Hypoplasia, and foliation

Defect

L1 (ECM adhesion protein)

L1CAM

CRASH syndrome with

Sztriha et al 2000

Callosal defect, retardation,

Adducted thumbs, spasticity,

And hydrocephaly

TABLE 3summary of genes affecting neurogenesis and brain organization

Mutation phenotype

Proliferation/apoptosis a

Gene

Murine

Human

Reference

TISH (unknown,

Tish

DC/SBH-like rat

Lee et al 1997

Recessive gene in

Mutant due to ectopic

Lee et al 1998

Seizure-prone rat)

Neural cell

Proliferation

EMX2 (transcription

difference between hypoxia and anoxia

EMX2

−/−: disorganized

A rare cause of

Granata et al 1997

Factor homologue

Cortex with abnormal

Open lipped

Mallamaci et al 2000

Of drosophila

Subplate and marginal

Schizencephaly

Segmentation gene

Zone development

Empty spiracles)

Affecting radial glia

Rb (oncogene

PRB

−/−: ectopic mitoses

Lee et al 1992

Regulating G1

And apoptosis in brain

Progression)

Caspase-3 (enzyme

CPP32

−/−: shows increased

Kuida et al 1996

Required for

Cell numbers,

Apoptosis)

Displaced neurons

Cyclin D2 [G1 active

Ccnd2

−/−: thinned cortex,

Huard et al 1999

Subunit regulating

Small cerebellum,

Cyclin-dependent

Reduced neural

Kinase 4 (cdk4)]

Proliferation, and

Increased apoptosis

Cyclin D1 (G1-active

Ccnd1

−/−: runted animal,

Sicinski et al 1995

Subunit regulating

difference between hypoxia and anoxia

Thinned cortex, motor

Cdk4)

Abnormalities

Suggesting spasticity