2.1 Antecedentes investigativos
2.1.4 Antecedente Regional
... introduction
As.we.have.described.earlier,.the.other.way.nerves.communicate.their.spike.signals.to.other.neu- rons,.muscles,.and.gland.tissues.is.by.chemical.synapses..There.are.two.major.categories.of.chemi-cal.synapses:.excitatory.and.inhibitory..Excitatory.synapses.act.to.cause.a.positive.action;.that.is,.
the.propagation.of.postsynaptic.nerve.spikes,.the.contraction.of.muscles,.or.the.secretion.of.glands..
Inhibitory.synapses.act.on.postsynaptic.neurons.to.inhibit.the.generation.of.postsynaptic.spikes.that.
are.stimulated.by.the.firing.of.excitatory.neurons..In.crustacean.neuromuscular.systems,.inhibitory.
synapses.can.prevent.or.reduce.muscle.contraction.by.direct.action.on.the.muscle.membrane.itself.
[Fatt.&.Katz.1953]..In.this.section,.we.will.describe.the.mechanism.by.which.excitatory.and.inhibi-tory.chemical.synapses.work.
Figure.3.9.illustrates.schematically.the.major.features.of.a.chemical.synapse..An.action.poten-tial. propagates. down. the. presynaptic. nerve. axon. and. the. membrane. depolarization. invades. the.
terminal.branches.that.are.terminated.in.synaptic boutons.(knobs)..Arrival.of.the.depolarization.
wave.induced.by.the.action.potential.causes.voltage-gated.calcium.channels.to.open.in.the.bouton’s.
membrane..The.influx.of.Ca++.causes.exocytosis.of.vesicles.filled.with.neurotransmitter molecules..
The.vesicles.discharge.their.contents.in.an.all-or-none.manner..In.cholinergic neurons,.each.vesicle.
holds.about.1,000.to.3,000.molecules.of.the.neurotransmitter,.acetylcholine.(ACh)..Each.vesicle.is.
said.to.hold.one quantum.of.neurotransmitter.
Alignment protein Synaptic vesicles Vesicle fusion
protein
Actin filaments Actin
filaments
Sub-synaptic Na+ channels Ca++
channel
Ca++
channel Synaptic
bouton
Dense body
Actin-binding protein Transmitter
Na+
SSM
Key:
Ca++
ions
Na+ ions
Vesicle fusion protein Ca++
B A
figuRe . (A).Schematic.cross.section.of.a.bouton.forming.a.chemical.synapse..SSM.is.the.subsynaptic.
membrane.across.which.the.neurotransmitter.(NT).molecules.diffuse.when.released..The.dots.in.the.synaptic.
vesicles.represent.NT.molecules..(B) Schematic.of.the.same.synapse.immediately.after.arrival.of.a.presyn-aptic.nerve.spike..The.paired.circles.in.the.plasma.membrane.represent.NT-activated.Na+.ion.gates;.two.NT.
molecules.are.required.to.cause.a.transient.opening.of.these.ion.gates..[Adapted.from.Northrop.2001..With.
permission.from.Taylor.&.Francis.]
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers The.released.neurotransmitter.molecules.diffuse.across.the.synaptic cleft.and.bind.to.receptor.
molecules.on.the.subsynaptic.membrane..These.receptors.are.ligand-gated, specific ion channels..
There.are.several.different.neurotransmitters.and.several.types.of.ion.channels..There.are.enzymes.
associated. with. every. chemical. synapse. that. act. to. destroy. the. released. neurotransmitter.. If. not.
destroyed,.the.receptors.in.the.postsynaptic.membrane.would.remain.bound.to.the.neurotransmitter.
molecules.and.the.synapse.would.be.effectively.blocked.
Acetylcholine. is. an. important. excitatory. neurotransmitter. in. neuromuscular. junctions. and.
nerve-nerve.excitatory.synapses..ACh.binds.to.ligand-gated.sodium.ion.channels,.causing.sodium.
ions.to.rush.in.through.the.SSM.and.depolarize.it..If.the.net.depolarization.reaches.the.transmem-brane.potential.firing.threshold,.a.postsynaptic.nerve.spike.or.a.muscle.action.potential.(and.twitch).
will.be.generated..The.transient.positive-going.Vm.is.called.an.excitatory postsynaptic potential.
(EPSP)..At.a.neuromuscular.junction,.about.150.quanta.of.ACh.are.released.at.the.arrival.of.a.motor.
neuron.spike.[Kandel.et.al..1991].
Gamma aminobutyric acid.(GABA).is.an.example.of.an.inhibitory.neurotransmitter.substance.
found.in.inhibitory.CNS.synapses..The.binding.of.GABA.to.SSM.“type.A”.receptors.allows.ligand-gated.chloride.channels.to.open,.causing.the.subsynaptic.transmembrane.voltage.to.rapidly.approach.
the.chloride.Nernst.potential..This.clamps.Vm.≈.ECl,.effectively.preventing.Vm.from.reaching.the.
firing.threshold.of.the.postsynaptic.cell..The.GABA.type.B.receptor.is.a.second-messenger system..
GABA.binding.to.the.B.receptor.activates.an.internal G-protein.and.an.internal.second.messen-ger.causes.potassium.channels.to.open.more.slowly,.driving.Vm.toward.EK.(about.−80.mV)..This.
hyperpolarization.is.generally.summed.in.the.postsynaptic.neuron.with.the.depolarizing.effect.of.
excitatory.inputs..The.negative-going.Vm.caused.by.GABA.B-binding.is.called.an.inhibitory post-synaptic potential (IPSP)..Neurotransmitters.are.presented.in.Table.3.4.[Kimball.2005p].
Many.animals.and.organisms.have.evolved.poisons.and.toxins.that.interfere.with.neurotransmis-sion,.including.jellyfish,.mollusks,.spiders,.snakes,.lizards,.and.bacteria..The.poisons.from.animals.
are. used.for. defense. and. for. prey. capture.. Some. of. these. poisons. block. synaptic.neurotransmit-ter-esterases,.others.bind.to.subsynaptic.ligand.sites.and.block.neurotransmitter.action,.and.others.
prevent.neurotransmitter.release..For.example,.bacterial.Botulinum toxin A binds.to.ACh.releasing.
boutons.and.prevents.ACh.release,.causing.flaccid.paralysis..Tetanus toxin, also.from.a.Clostridium table .
some mammalian neurotransmitters and neuromodulators
neurotransmitter acts on
ACh Skeletal.muscle
Preganglionic.neurons.of.the.autonomic.NS Postganglionic.neurons.of.the.parasympathetic.NS Certain.CNS.neurons
Glutamic.acid. CNS.excitatory.synapses
GABA,.glycine CNS.inhibitory.synapses.
Norepinephrine Postganglionic.neurons.of.the.sympathetic.branch.of.the.
autonomic.NS Certain.CNS.synapses
Dopamine Certain.CNS.synapses
Serotonin.(5HT) Certain.CNS.synapses
Histamine Certain.CNS.synapses
Peptide.hormones:vasopressin.(ADH),.oxytocin,.
gonadotropin-releasing.hormone,.angiotensin.II,.
cholecystokinin,.substance.P,.2.en-kephalins.(met-enkephalin,.leu-enkephalin)
Various.target.sites.in.the.body
bacteria,.selectively.binds.to.and.enters.spinal.neurons,.where.it.blocks.glycine.release.and.causes.
spastic.paralysis.[Hardman.et.al..1996]..(The.neurotransmitter.glycine.causes.inhibition.by.increas-ing.chloride.conductance.)
... neural transmembrane chemical signal Receptors
By.now,.you,.the.reader,.are.aware.that.membrane.proteins.are.extremely.diverse.and.plentiful..One.
reference.cites.608.protein.transmembrane.structures.[PDBTM.2006]..Transmembrane.molecular.
receptor.(TMMR).molecules.are.one.factor.that.makes.metazoan.life.possible..For.an.organism.to.
act.as.an.entity.rather.than.an.amorphous.collection.of.cells,.the.cells.must.have.a.command,.con-trol,.and.communication.(C3).system.to.coordinate.organismal homeostasis.(as.opposed.to.cellular homeostasis).and.behavior..The.organismic-level.C3.is.carried.out.in.part.by.a.nervous.system.in.
higher.metazoans,.as.well.as.by.hormonal.and.chemokine.signals.
Neural.and.hormonal.signals.are.transduced.by.cells’.transmembrane.signal.receptor.(TMSR).
molecules..That.is,.the.TMSR.molecules.are.molecular transducers,.converting.the.binding.of.the.
signal. molecule. to. another. molecular. event. within. the. cell.. Receptors. generally. have. very. high.
specificity.for.their.signal.molecules.(ligands),.which.bind.to.the.extracellular.part.of.the.TMSR.and.
cause.the.inner.portion.of.the.receptors.to.activate.(or.suppress).cell.activities.such.as.expression.of.
specific.proteins.
The.structures.of.many.TMSRs.are.known;.they.are.composed.of.two.or.more.protein.subunits.
that.operate.collectively..The.genes.coding.many.receptors.and.the.chromosomes.where.they.are.
located. have. been. listed. [SenseLab. 2006].. TMSRs. have. three. structural. domains:. extracellular (contains.a.binding.site.for.the.target.ligand),.transmembrane (the.molecules.that.penetrate.the.cell.
membrane),.and.the.intracellular.domain..The.event.of.a.ligand.binding.to.the.extracellular.domain.
is.communicated.through.the.transmembrane.domain.to.the.intracellular.domain.
... g-protein-coupled Receptors
A.major.class.of.TMSR.is.called.the.G-protein coupled receptors (GPCRs),.or.seven transmembrane receptors.(7TMRs),.also.known.as.heptahelical receptors..This.class.of.TM.receptor.is.ubiquitous.in.
eukaryotic.cells..7TMRs.can.be.activated.by.photons,.odorants,.neurotransmitters,.hormones,.certain.
glycoproteins,.and.chemokines..The.7TMRs.possess.seven.linked,.helical.peptides.that.penetrate.the.
lipid.bilayer.of.the.cell.membrane..This.class.of.receptors.has.a.free.end.and.three.loops.that.protrude.
into.the.extracellular.fluid;.also,.a.free.end.and.three.loops.project.into.the.cytosol..The.extracellular.
parts.of.the.7TMRs.can.be.glycosylated..The.extracellular.loops.also.contain.two.cysteine.residues.
that.enable.stable.disulfide.bonds.to.form,.making.the.7TMRs.more.chemically.stable.
G-proteins. are. called. that. because. they. bind. to. the. guanine nucleotide phosphates,. GDP,. and.
GTP..The.details.of.the.actual.transduction.mechanism.of.GPCRs.are.not.completely.understood..It.is.
thought.that.once.the.ligand.binds.within.the.transmembrane.domain,.the.GPCR.conformation.shifts.
and.somehow.activates.the.G-protein,.which.is.bound.to.the.inner.domain.of.the.receptor..The.inactive.
G-protein.has.a.heterotrimeric.(α,.β,.γ).structure;.it.is.associated.with.the.C-terminal.(inner).end.of.each.
7TMR..There.are.about.23.different.Gα.subunits.in.mammals,.5.β,.and.14.γ.subtypes,.which.have.been.
found.in.a.wide.variety.of.combinations.[McCudden.et.al..2005;.Preininger.&.Hamm.2004].
The.activated.G-protein’s.Gα.subunit.exchanges.guanine diphosphate.(GDP).for.GTP..The.Gα-GTP.splits.from.the.Gβγ.dimer..Both.these.altered.G-proteins.detach.from.the.inner.7TMR.and.can.
induce.intracellular.signaling.events..Once.the.G-protein.is.activated,.the.7TMR.can.uncouple.the.
ligand.and.go.back.to.its.“ready”.state,.or.it.can.stay.active.and.activate.another.nearby.G-protein.
The.activated.G-protein.initiates.the.production.of.a.second messenger.(SM).molecule..One.
common.SM.is.cyclic.AMP.(cAMP),.which.is.produced.by.the.enzyme.adenyl cyclase (AC) using.
ATP..AC.is.bound.to.the.inner.cell.membrane.near.the.7TMR..Another.SM.molecule.is.inositol 1,4,5-triphosphate (IP3)..The.SM.molecule,.in.turn,.can.trigger.a.sequence.of.intracellular.events.
such.as.phosphorylation.and.activation.of.enzymes.or.the.release.of.calcium.ions.into.the.cytosol.
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers from.stores.inside.the.ER..The.SM,.cAMP, activates.the.transcription factor (TF),.cAMP response element binding protein (CREB),. which. is. bound. to. its. response. element,. 5′TGACGTCA3′,. in.
the.promoters.of.those.genes.that.are.supposed.to.respond.to.the.signaling.ligand..Once.CREB.is.
activated,.it.turns.on.gene.transcription,.causing.the.cell.to.make.the.desired.proteins.and.RNAs.
required.by.the.signal.ligand.that.has.bound.to.the.7TMR.on.the.cell’s.surface.
Another.layer.of.complexity.in.the.picture.of.cellular.signal.transduction.is.introduced.by.the.
observation.that.the.β-arrestin.proteins.modulate.second-messenger.biochemical.signals,.making.
the.description.of.second-messenger.networks.even.more.complex..The.arrestins.regulate.aspects.
of.cell.motility,.chemotaxis,.apoptosis,.and.probably.many.other.cellular.functions.[Lefkowitz.&.
Shenoy.2005]..But.what.regulates.the.arrestins?
(The.reader.interested.in.pursuing.the.topic.of.G-proteins.in.depth.should.read.the.review.paper.
by.McCudden.et.al..[2005]).
... summary
In.concluding.this.section,.we.stress.the.incredible.complexity.and.diversity.of.intercellular.chemi-cal.communications.by.listing.the.following.categories.of.membrane.receptors.(the.numbers.of.each.
type. of. receptor. known. are. in. parentheses).. The. entries. are. for. receptors. for. neurotransmitters, neuromodulators, hormones,.and.signal substances.
5-Hydroxytryptamine. (5HT). receptors. (14),. Acetylcholine. receptors. Muscarinic. (5),. Acetylcholine.
receptors,. Nicotinic. (8),. Adenosine. receptors. (4),.α1-Adrenoreceptors. (3),.α2-Adrenoreceptors. (3),.
β-Adrenoreceptors.(3),.Angiotensin.receptors.(2),.Atrial.natriuretic.peptide.receptors.(2),.Bombesin.
receptors. (3),. Bradykinin. receptors. (2),. Calcitonin,. amylin,. CGRP. &. adrenomedullin. receptors. (4),.
Cannabinoid.receptors.(2),.CC-Chemokine.receptors.(11),.CX3C-Chemokine.receptors.(5),.Chemotac- tic.peptide.receptors.(3),.Cholecystokinin.&.Gastrin.receptors.(2),.Corticotropin.releasing.factor.recep-tors. (2),. Dopamine. receptic.peptide.receptors.(3),.Cholecystokinin.&.Gastrin.receptors.(2),.Corticotropin.releasing.factor.recep-tors. (5),. Endothelin. receptic.peptide.receptors.(3),.Cholecystokinin.&.Gastrin.receptors.(2),.Corticotropin.releasing.factor.recep-tors. (2),. Glycine. receptic.peptide.receptors.(3),.Cholecystokinin.&.Gastrin.receptors.(2),.Corticotropin.releasing.factor.recep-tors. (1),. GABAA. receptors.
(2),.GABAB .receptors.(1),.Galanin.receptors.(3),.Glutamate.receptors,.ionotropic.(4),.Glutamate.recep-tors,.metabotropic.(8),.Glycoprotein.hormone.receptors.(3),.Histamine.receptors.(3),.Ins(1,4,5)P3(IP3).
receptors.(3),.Leukotriene.receptors.(3),.Lysophospholipid.receptors.(5),.Melanocortin.receptors.(5),.
Melatonin.receptors.(3),.Neuropeptide.Y.receptors.(6),.Neurotensin.receptors.(2),.Neurotrophin.recep- tors.(4),.Opioid.&.opioid-like.receptors.(4),.P2X.receptors.(transmitter-gated.channels).(7),.P2Y.recep-tors.(G-protein-coupled).(6),.Peroxisome.proliferator.activated.receptors.(3),.Prostanoid.receptors.(8),.
Protease-activated.receptors.(4),.Ryanodine.receptors.(3),.Somatostatin.receptors.(5),.Steroid.hormone.
receptors.(4),.Tachykinin.receptors.(3),.Thyrotropin-releasing.hormone.receptors.(2),.Vasoactive.inten-tinal.peptide.&.pituitary.adenylate.cyclase.activating.peptide.receptors.(3),.Vasopressin.&.Oxytocin.
receptors.(4)..[SenseLab.2006. Quoted.with.permission.]
The.description.of.cell.receptor.proteins,.how.they.work.intracellularly,.and.how.they.are.regu-lated.is.a.fascinating,.complex.discipline.of.molecular.biology.and.physiology..Cell.receptor.protein.
functions.probably.hold.the.answer.to.what.regulates.stem.cell.differentiation,.and.hence,.embry-onic.development.
. RevieW of cell RepRoDuction 3.8.1 the cell cycle: Mitosis
The.process.of.eukaryotic.cell.mitotic.division.is.a.complex.and.carefully.regulated.event..Cells.
such.as.stem.cells of.various.types.(see.Chapter.10,.Section.10.4),.embryonic.cells,.mature.epithelial.
cells,.and.corneal.cells.divide.continuously;.other.cells.such.as.neurons.and.erythrocytes.do.not.
divide.once.they.have.matured..All.cells.require.external.molecular.signal.cells.to.trigger.division..
For.example,.cells.such.as.fibroblasts.are.stimulated.to.divide.(enter.the.cell cycle).by.external.regu-latory.signals.from.platelets.associated.with.tissue.damage.
The.cell.cycle.leading.to.cell.division.has.five.distinct.morphological.and.biochemical.stages..
These.are
G1:.Growth.and.preparation.for.chromosomal.(genomic).replication..This.is.also.called.G1 interphase. The.G1.chromosomes.each.have.one.chromatid (n.=.1).
S:.DNA.replication.and.synthesis.of.centrosomes..Also.part.of.interphase.
G2:.The.cell.is.preparing.for.mitosis..By.G2 interphase,.the.cell.has.duplicated.its.DNA.
and.is.2n. Each.chromosome.now.has.two.chromatids.joined.by.a.centromere.
M:.The.mitotic.events.occur.(prophase, metaphase, anaphase, telophase, and cytokinesis).
G0:.Quiescent.phase;.no.further.entry.into.the.cell.cycle..Some.cells.can.be.stimulated.to.
reenter.the.cell.cycle.and.divide.by.external.signals.
Special.cytosolic.proteins.called.cyclins.regulate.the.cell.cycle.internally:.Cyclin D.(a.G1.cyclin),.
cyclins E and A (S-phase.cyclins),.cyclins A and B.(M-phase.cyclins)..In.addition,.there.are.cyclin-dependent kinases (Cdks). (A.kinase.is.an.enzyme.that.phosphorylates.a.target.molecule.).These.
include.Cdk4.(used.in.G1),.Cdk2.(used.in.S-phase),.and.Cdk1.(used.in.M-phase)..There.is.also.the.
anaphase-promoting complex (APC).(aka.the.cyclosome),.which.triggers.biochemical.events.that.
allow.the.sister chromatids.to.separate..APC.also.degrades.the.mitotic.cyclin B..Figure.3.10.illus-trates.the.cell.cycle.schematically.and.shows.when.the.cycle.regulating.molecules.is.active.
Mitotic.events.in.the.cell.cycle.visible.in.the.light.microscope.are.also.described.with.tradi-tional.nomenclature:
Interphase:.Chromosomes.are.not.clearly.discernable.in.the.nucleus,.although.the.nucleo-lus.may.be.visible..A.pair.of.centrioles.may.be.visible..The.2n.cell.is.engaged.in.metabolic.
activity.preparatory.to.mitosis;.its.mass.may.double..(Plant.cells.lack.centrioles.)
•
•
•
•
•
•
Prophase Metaphase
Anaphase Telophase
G0 (Quiescent) S
G1 G2
MMitosis Cyclin A
Cdc2
Cyclin A Cdk2
Cyclin E Cdk2
Cyclin D Cdk 4/6 Cyclin B Cdc2
figuRe .0 Generalized. time. line. for. the. mitotic. cell. cycle. showing. when. regulatory. molecules. are.
active.
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers Prophase: Chromatin.in.the.nucleus.becomes.visible.as.chromosomes..(Chromatin.is.a.
mass.of.uncoiled.DNA.and.the.histone.proteins.associated.with.it.).The.nucleolus.disap-pears..Centrioles.begin.moving.to.opposite.ends.of.the.cell,.and.microtubule fibers.are.
visible.extending.from.the.centromeres..Some.fibers.cross.the.cell.and.form.the.mitotic spindle. (Microtubule.fibers.are.made.from.α- & β- tubulin.proteins..See. Chapter.7,.Sec-tion.7.2.4.2.)
Prometaphase:.The.nuclear.membrane.dissolves.at.the.beginning.of.prometaphase..Pro-teins.attach.to.the.centromeres, creating.the.kinetochores. Microtubules.from.the.centri-oles attach.to.the.kinetochores.and.begin.moving.the.chromosomes.
Metaphase: Spindle.fibers.align.the.chromosomes.along.the.metaphase plate.that.bisects.
the.former.nucleus..This.geometry.ensures.that.in.the.next.phase.when.the.chromosomes.
are.separated,.each.new.daughter.nucleus.will.receive.one.complete.set.of.chromosomes.
Anaphase:.The.paired.chromosomes.are.separated.at.the.kinetochores.and.pulled.to.oppo-site.ends.of.the.cell.by.the.kinetochore microtubules..This.motion.results.from.the.coordi-nated.shortening.of.the.kinetochore.microtubules.and.the.polar.microtubules.anchored.to.
two.ends.of.each.chromosome.called.a.telomere. In.young.human.cells,.the.telomere.Nt.sequence.5′. TTAGGG.3′.is.repeated.thousands.of.times..Every.time.the.cell.divides,.it.looses.about.16.of.these.
repeat.sequences..When.the.telomere.repeats.are.gone,.the.cell.can.no.longer.divide..(See.Kimball.
2006d.for.the.details.of.how.telomere.shortening.occurs.and.how.it.inhibits.mitosis.)
The.enzyme.telomerase.can.reconstitute.the.telomeres.by.adding.the.telomere.repeat.sequence.
to. the. 3′. end. of. the. DNA.. Telomerase. is. a. ribonucleoprotein;. in. mammals,. it. contains. a. single.
snoRNA.strand.with.the.Nt.sequence.AAUCCC.that.guides.the.insertion.of.TTACCC.on.the.end.
of.the.DNA..The.protein.component.of.telomerase.is.telomere reverse transcriptase.(TERT),.which.
catalyzes.the.insertion.
Telomerase.is.generally.not.found.in.adult.somatic.cells..However,.it.is.found.in.cells.that.must.
divide.many.times,.including.embryonic stem cells.and.cells.involved.with.gametogenesis. It.is.also.
present.in.unicellular.eukaryotes.and.cancer.cells..It.has.been.found.that.85.to.90%.of.cancer.cells.
have. somehow. regained. the. ability. to. synthesize. high. levels. of. telomerase. throughout. their. cell.
cycle,.ensuring.their.ability.to.keep.reproducing.
Worn-out. and. damaged. cells. are. removed. from. the. population. by. programmed cell death (PCD),.or.apoptosis,.which.was.described.in.detail.in.Chapter.2,.Section.2.5.2.
3.8.2 Meiosis
Meiosis. is. a. cell-division. protocol. used. in. animal. embryogenesis. to. produce. haploid. sperm. and.
eggs.from.diploid,.primordial.germ.cells..It.also.promotes.genetic diversity. Meiosis.consists.of.two.
•
sequential.nuclear.divisions.that.reduce.the.number.of.chromosomes.in.the.cell.nucleus.from.2n.to.
the.haploid.number,.n..Chromosome.shuffling.also.occurs..First,.two.diploid.cells.are.produced,.and.
then.in.a.second.division.four.haploid.cells.result.
Figure.3.12.illustrates.the.process.far.more.eloquently.than.a.verbal.description..Note.that.there.
are.important.differences.between.meiosis.and.mitosis,.although.they.both.involve.tubulin.“traction.
motors”.to.separate.the.genetic.material..Meiosis.is.subdivided.into.Meiosis I.(M1).and.Meiosis II.
(M2)..Referring.to.Figure.3.12.(top.left),.a.diploid.(2n).progenitor.cell.in.meiotic interphase dupli-cates.its.chromosome.pairs.and.becomes.4n..The.tetrads.formed.are.held.together.by.proteins.called.
cohesins.
In.meiotic.Prophase I,.the.chromatin.condenses.and.organizes.(the.cell.in.the.figure.has.n.=.2)..
During.chromosome.duplication.in.Prophase I,.crossing over.can.occur.in.which.chromatids.in.a.
tetrad.actually.cross,.stick.together,.and.swap.genetic.material.between.chromatids,.as.illustrated.
in.Figure.3.13.
Late meiotic prophase I.is.also.called.Diakinesis. The.nuclear.membrane.breaks.down,.and.the.
centromeres.of.the.paired.chromatids.become.attached.to.spindle.fibers.at.their.kinetochores..The.
dividing.cell.now.progresses.to.Metaphase I. Pairs.of.chromatids.line.up.at.the.center.of.the.cell.on.
the.metaphase plate. In.the.figure,.the.red/blue.colors.show.where.crossover.has.occurred.
In.Anaphase I,.the.spindle.traction.motors.exert.force.and.separate.the.joined.pairs.of.chroma-tids.(dyads)..Each.centromere.does not.divide.in.meiotic.anaphase;.they.do.in.mitosis..In.Telophase I, cytokinesis.occurs,.yielding.two.daughter.cells.each.with.four.chromatids..A.nuclear.membrane.
may.form.here.in.some.species.
The.second.stage.of.meiosis.has.features.similar.to.mitosis..In.meiotic Prophase II, the.chro-mosomes.condense.and.any.nuclear.membrane.breaks.down..In.Metaphase II,.the.dyads.line.up.
Prophase Metaphase
Telophase/Cytokinesis Actin
Interphase
Daughter cells (2n) S-Phase
(2n) (2n)
(2n)
(2n)
(n)
(n)
Anaphase
G2 Interphase G1 Interphase
figuRe . (See.color.insert.).A.schematic.of.the.cell.cycle.showing.what.happens.to.the.chromatids.in.
mitosis..See.text.for.further.description.
Introduction to Molecular Biology, Genomics and Proteomic for Biomedical Engineers
parallel.along.the.metaphase.plate.connected.to.spindle.fibers.attached.to.the.centrioles..The.dyads.
are.pulled.apart.at.their.centromeres.and.single.chromatids.are.pulled.toward.the.centrioles.in.Ana-phase II. In.Teloare.pulled.apart.at.their.centromeres.and.single.chromatids.are.pulled.toward.the.centrioles.in.Ana-phase II,.nuclear.membranes.again.can.form,.and.cell.division.occurs,.yielding.a.
total.of.four.haploid.(germ).cells.(n = 2.in.our.example).from.one.progenitor.cell.
Note.that.meiosis.“shuffles”.the.genomic.deck.in.producing.sperm.and.eggs..The.full.meiotic.
process.in.humans.can.theoretically.produce.2n.=.223.=.8,388,608.different.types.of.haploid.gamete.
genomes.(without.crossing.over)..With.crossovers,.the.number.becomes.astronomical;.in.fact,.there.
is.a.vanishingly.small.probability.that.any.of.the.billions.of.sperm.a.man.produces.in.his.lifetime.
will.have.an.identical.gene.content..The.same.goes.for.the.hundreds.of.eggs.that.mature.over.the.
lifetime.of.a.woman.[Kimball.2006e].
It.would.be.naive.to.expect.that.processes.as.biochemically.and.physically.complex.as.sper-matogenesis. and. oogenesis. are. without. error.. Perhaps. 10. to. 20%. of. all. human. zygotes contain.
chromosome.abnormalities..These.genomic.errors.are.the.most.common.cause.of.early.spontane-Late Prophase I Metaphase I Anaphase I
Cytokinesis/Telophase I Metaphase II
Anaphase II
4 Haploid daughter cells A
A
B
B Telophase/
Cytokinesis II
Interphase (G1 & G2) Early Prophase I Mid-Prophase I
a b
c d
figuRe . (See.color.insert.).Schematic.of.how.meiosis.produces.four,.haploid.daughter.cells..The.fates.
of.the.chromatids.are.shown..See.text.for.further.description.
ous.abortion.(35%.of.the.cases)..According.to.Kimball.[2006e],.chromosome.errors.in.zygotes.arise.
from.errors.in.meiosis,.usually.Meiosis.I..The.errors.occur.with.90%.greater.frequency.in.oogenesis.