Neurogenesis and Migration

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Neurogenesis and Migration

• Jeff Corwin
• 924-1568
• jcorwin_at_virginia.edu
• MR-4, 5th Floor, Rm 5150
• (Next to Kevin Lee)

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• The human brain contains
• 100 billion neurons.
• On average each neuron make contacts with 10,000
  other neurons.
• Therefore, its estimated that the human brain
  contains 1 quadrillion synapses.
• (Human brain also contain 1 trillion glial
  cells.)

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• There are 100,000,000,000 neurons in the human
  brain.
• A 9-month human gestation period is 403,200
  minutes. (280 days, with 24 hours/day, and 60
  minutes/hour).
• Therefore, if all the neurons in the human brain
  were produced before birth, the average rate of
  production would be 250,000 neurons/minute.

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Primary Neurulation
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Primary Neurulation
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The Development of the Vertebrate Spinal Cord
Alar
Basal
General Rule 1 Alar plate gt Sensory Basal plate
gt Motor
General Rule 2 No cell in the vertebrate NS is
more than one neuron from the CNS. (with one
system exception).
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The Development of the Vertebrate Brain
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General Rule 3

• Most CNS neurons are generated far from the
  sites theyll occupy in the adult CNS.

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General Rule 4

• Large, principal neurons are generated early
  in development.
• Usually small interneurons are generated late.

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Current understanding arose from

• descriptive neuroanatomy
• 3H-thymidine and BrdU "birthdating"
• serial section electron microscopic (EM)
  reconstructions
• reconstituted cultures
• time-lapse viewing of cultured slices.

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Stage 20 (E12.5) Rat (section prepared by
Themis Karaoli).
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A father and daughter effort by Fred (1935) and
Mary Sauer (1959) over a 24-year period
eventually convinced others of the
pseudostratified nature of the early neural tube
and the role of nuclear movements in vertebrate
neurogenesis.
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G1
S G2
M
G1
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Kathy Tosney
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Anti-phospho-histone H3 in a Stage 20 (E12.5)
Rat (prepared by Themis Karaoli.
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What are the functions of the interkinetic
nuclear migrations that occur in all developing
vertebrate neuroepithelia?
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Cell division orientation can influence the fate
of the progeny produced by a division.
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How cell division orientation influences cell fate
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Neurogenesis and Migration in the Cerebral Cortex

• The single-cell thick neuroepithelium persists to
  the three-vesicle stage of brain development
  (General "Rule 5).
• Then the preplate begins to develop at the
  outside (i.e., away from the apical ventricular
  surfaces of the cells).
• The preplate consists of an outer marginal zone
  containing large, stellate Cajal-Retzius cells
  and a deeper zone of cells called the subplate.

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• Next, new postmitotic neurons accumulate in the
  preplate to form the cortical plate.
• The expanding cortical plate progressively
  divides the preplate region into the marginal
  zone composed of Cajal-Retzius cells and subplate
  cells (The subplate cells will die off later).
• Beneath that is the intermediate zone composed of
  increasing numbers of incoming axons and beneath
  that is the proliferative ventricular zone.

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Migration in the forming Cerebral Cortex

• The accumulation of new neurons in the cortical
  plate results in great expansion of the
  presumptive cerebral cortex.
• Radial glia span the full thickness of the
  forming cerebral cortex (3 mm) and serve as
  guides for the migration of neurons from the
  ventricular zone outward as shown by careful
  serial section EM reconstructions by Rakic.

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From the work of Pasko Rakic
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The Cerebral Cortex forms in an inside-out
pattern

• When cells go through their final (terminal)
  cell division they will remain maximally labeled
  by a correctly timed pulse of 3H-thymidine.
• Other cells that continue to divide will dilute
  the label during the time after the pulse.
• Jay Angevine Richard Sidman, and later Pasko
  Rakic, and Joseph Altman Shirley Bayer mapped
  the eventual adult locations of neurons that had
  completed their terminal cell division at various
  times during development.

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From the work of Angevine Sidman
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From the work of Pasko Rakic
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Secondary neurogenesis

• Initially proliferation occurs exclusively in the
  ventricular zone (VZ, from E11 to 14 in mouse)
• Later in development (at E16 in mouse), the
  Subventricular zone (SVZ) becomes an important
  secondary site of proliferation.

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Secondary neurogenesis

• In the mouse proliferation ceases in the VZ at
  E19, but it continues in the SVZ at substantial
  levels into the 2nd postnatal week in mouse, and
  in humans it continues through the 2nd year of
  life.
• Secondary neurogenesis gives rise to many small
  neurons (e.g., hippocampal and some cerebellar
  granule cells).

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Neurogenesis in the adult brains of birds and
mammals can occur in the subventricular zone and
some may also occur in the ventricular zone.
From Arturo Alvarez-Bullya
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General Rule 6

• The neurons in the brainstem nuclei also arise
  through production in the ventricular zone and
  migrate over considerable distances to their
  ultimate location.
• Often the neurons of a nucleus all have the same
  birthday, i.e. time in development when they
  were produced by a terminal cell division.

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The Five Major Cell Types of the Cerebellar Cortex

• Purkinje cells
• Granule cells
• Stellate cells
• Basket cells
• Golgi cells
• Parallel fibers
• Climbing fibers
• Mossy fibers

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Please see the "Cerebellum Fact Sheet" for
further details on the form and functions of the
circuitry of the cerebellar cortex.
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Neurogenesis and migration in the cerebellum

• Purkinje cells arise via early neurogenesis in
  the ventricular zone above the IVth ventricle
  (from E11 to E14 in mouse).
• The great majority of the cerebellar granule
  cells are derived from proliferative cells that
  migrate from the Rhombic Lip to lie external to
  the Purkinje cells.
• Those proliferative cells form the External
  Germinal Layer (EGL).

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3
2
1
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Neurogenesis and migration in the cerebellum
(continued)

• In mice the EGL is 1 to 2 cells thick at E16, but
  proliferation there continues until P15 giving
  rise to granule cells that eventually outnumber
  the Purkinje cells at least 2501 in the mouse
  (at least 4001 in humans).
• Migrating granule cells descend from the EGL
  along Bergmann glial fibers until they come to a
  position below the somata of the Purkinje cells.
  
• In humans there are granule cells migrating from
  the EGL as late as 2 years after birth.

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• The development of reconstituted migratory
  cultures of cerebellar granule cells allowed Mary
  Beth Hatten and her coworkers to ask how neurons
  adhere to glial fibers.
• Tests of antibodies to NCAM, N-cadherin, and L1
  did not interfere with migration, but an
  antiserum they raised against cerebellar granule
  cells inhibited migration significantly.

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• They presumed that their antiserum bound to a new
  adhesion molecule that functioned in migration,
  so they absorbed the antiserum with other neural
  cells and other cell types, in order to try to
  remove any antibodies from the serum that might
  have recognized common cell adhesion molecules.
• That strategy left them with an antiserum that
  labeled a single band of 100 kDa, which they
  named astrotactin.

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The Birth of Childhood

• Neurogenesis in the brains of all primates occurs
  at high rates before birth.
• As a result the brain-weights/ body-weight ratios
  of newborn apes and humans are comparable.
• The rate of neurogenesis decreases substantially
  after birth in apes, but it continues through the
  2nd year of life for humans.

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The Birth of Childhood (continued)

• The continuation of a high rate of neurogenesis
  after birth of humans is responsible for adult
  human brain-weight / body-weight ratios that are
  3.5 times those of other adult primates.
• It has been suggested that the increased capacity
  for learning that originated through the
  continuing high rate of postnatal neurogenesis
  in humans resulted in the development of
  childhood.

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The Birth of Childhood (continued)

• Childhood can be viewed as a stage in development
  unique to humans.
• Childhood is interposed between infancy, ending
  in 3 year olds with weaning, and the juvenile
  stage, beginning in 7 year olds, with the
  development of the capacity to gather food
  independently of adults.