6 - Cell Migration

What is cell migration?

Migration of neuronal cells to their positions and then differentiation into layer-specific neurons

When is the peak of migration?

Month 3-5 of gestation

What factors determine the preciseness of migration?

Timing and direction

What are the three main steps of migration?

Extension of leading process, nucleokinesis and retraction of trailing processes

What molecular mechanisms does migration depend on?

Cell cycle control, interaction with ECM proteins. andgrowth factor availability

Where does passive migration occur?

Non-laminated areas of the brain

What is passive migration?

Cells born first are pushed up by the cells growing underneath them

Where does active migration occur?

Laminated brain regions

What are the two types of active migration??

Radial and tangential

What is radial migration?

Follow a trajectory that is perpendicular to the surface of hte brain/ventricular surface

What. istangential migration?

Follow a trajectory that is parallel to the surface of hte brain/ventricular surface and is perpendicular to the radial glia fibers

What are the two kinds of radial migration?

Somal translocation and glia-guided migration

What is somal translocation?

long, radially oriented basal process that terminates at. thepial surface and a short, transient trailing process

When does somal rtanslocation occur?

Early stage of embryonic development

When does glia-guided migration occur?

Later in development

What is glia0guided migration?

Radial glial fibres form a scaffold guiding newly formed neurons throguh the developing cortex followed by terminal translocatoin

What is tangential migration?

Cells migrate parallel to the surface of the cortex through neurophilic migration

What do NMDs typically develop?

Week 12-16 of gestation

What are NMDs?

Spectrum of malformations caused by a defect in neuronal migration during embyronic development

What is heterotopias?

Cells accumulating in unusual brain areas forming inappropriate or no synaptic connections

What hpannes to neurons in MNDs?

Migrate to the wrong locations or at the wrong time

How are NMDs classified?

Based on visible morphologic cortex anomalies

What is a sulcus?

Depression in the surface of the brain

What is a gyrus?

Ridge on the cerebral cortex

Why is convolution important?

Surface area to volume ratio, allow cells access to veins/capillaries, creation of networks/synaptic connections

What is the overview of lissencephaly?

Lack of normal cortical convolutions

What is agyria?

Absence of gyri and sulci on the surface of the brain

What is pachygyria?

Few broad, flat gyri and shallow sulci

What is the cerebral thickness/layering like in lissencephaly?

Thicker than usual and abnoraml laminar organization

What are the three characteristics of lissencephaly?

Cerebral surface, cerebral thickness/layering, and enlarged ventricles

What is classical LIS?

Agyric or pachygyric regions, thick cortex, and disturbed composition of the cortical layers (4 instead of 6)

What causes classical LIS?

Undermigration

What causes the thickened cortex in classical LIS?

Increased gray matter

What are the cortical layers like in classical LIS?

Four immature layers of neurons instead of the normal 6 highly organized layers

What is cobblestone LIS?

Absent/diminished sulcation, disorganized/unlayered cortex, top of brain is bumpy

What causes cobblestone LIS?

Overmigration

Where do neurons move into in cobblestone LIS?

TOo far into subpial space

What are the layers like in cobblestone LIS?

Still have 6 layers but are not as defined

What allows neurons to migrate to the subpial space in LIS?

Basal lamina breakdown caused by an error in O-glycosylation

What typically occurs when neurons reach the basal lamina when migrating?

Repulsive cues telling cells to stop migrating

What is glycosylation?

Process in which carbohydrate molecules are attached to a protein by glycotransferase enzymes

What happens when glycosylation does not occur/has errors?

Changes protein function, structure, integrity, roles, etc.

What is muscular dystrophy a clinical sign for?

Cobblestone LIS

What are the two components of dystroglycan?

Alpha-dystroglycan and beta-dystroglycan

What must occur to both components of dystroglycan to function?

Glycosylated by glycotransferase

What happens when alpha-dystroglycan is not glycosylated?

Does not bind to ECM and disrupts basement membrane integrity and allows overextended migration of neurons

What two genes are implicated in LIS?

LIS1 and DCX

What are the DCX LIS1 genes involved in?

Microtubule-associated protein involved in nucleokinesis

What is the severity of LIS1 mutations?

Greater posterior than anterior severity

What is the severity of DCX mutation?

Greater anterior than posterior severity

What are environmental factors associated with NMDs?

Hypoxia, heavy metals, in utero viral infection, radiation, etc.

What happens when a fetus is exposed to GCs prior to mid-gestation?

Well-tolerated due to GC degreading enzymes in the placenta and fetal brain

What can steroid and stress exposure cause in a fetus?

Deficits in brain development such as reduced cortical thickness and delayed myelination

What are the effects of GCs on a fetus mid-gestation and onwards?

Increased GC receptors leads to increased susceptibility to GCs

What does GC binding lead to?

Increase expression in CaD expression

What is the role of CaD?

Negatively regulates function of myosin II in the leading process which regulates radial migration and actin-myosin interaction

What happens when CaD is increased by GCs?

CaD inhibits interactions between actin and myosin II in radially migrating neurons and disrupts migration

What is BrdU used to identify?

Proliferating cells

How are USWs used to detect neuronal migration patterns?

USW are high frequency mechanical vibrations used to see if it affects migration

What happens when USW is used for a long period of time?

Significant number of neurons fail to migrate properly

What are symptoms of LIS?

Short lifespan, acquired microcephaly, low muscle tone, paucity of movement, seizures, autism and schizophrenia

How is LIS diagnosed?

Neuroimaging

What is the treatment of LIS?

Supportive care and medication to control seizures