Brain Development: Normal Processes and the Effects of Alcohol ...

Neurogenesis and the Process
of Cell Type Specification
Neurogenesis comprise s th e productio n o f neuron s
and gli a tha t wil l reside i n a structure; this i s analogous
to organogenesis, which is the production of cells
that wil l constitut e a n organ . Thus, neurogenesis includes
the proliferatio n o f neural precursors, the fat e
decision, th e migration , differentiation , an d some -
times deat h o f th e cells . Mos t neurona l precursor
cells are generated in the proliferativ e zones that line
the inne r surface o f the neura l tube (se e Chapters 2,
11, and 12) . In thes e zones , precursor cells undergo
mitosis, wit h "symmetric" divisions, producing more
precursors. Eventually, some precursors begin "asymmetric"
divisions , with one daughte r cel l exitin g th e
cell cycl e and the proliferativ e zone, and then begin -
ning the transformatio n into particular types of neurons
o r gli a (Cavines s e t al. , 1995 ; Ohnum a an d
Harris, 2003). The origina l size of the progenitor pool
combined wit h th e duratio n o f neurogenesis o f any
given par t o f the brai n predict s it s size (Finla y an d
Darlington, 1995 ; Finlay et al, 2001).
Not every precursor cel l i n the nervou s system differentiates.
In some regions of the brain, stem cells remain
undifferentiate d throughou t th e lif e o f th e
animal, and recent work suggests that these cell s can
be presse d int o service to effec t repair s for damaged
neural circuit s even i n the adul t brain (e.g. , Alvarez-
Buylla and Garcia-Verdugo, 2002; Gage, 2002; Picard-
Riera e t al. , 2004) . That is , neuronal ste m cell s may
provide a substrat e fo r compensator y plasticit y i n
some systems of the brains of adults.
We concentrat e her e o n mechanism s tha t con -
trol th e assignmen t o f cel l identity , with particular
attention pai d to how the proces s may regulate itself
if disturbance s occur . Researcher s firs t frame d th e
question o f cell specificatio n in term s o f where cel l
specification occurs . Conceivably , thi s decision i s (a)
intrinsic, suc h tha t specifi c precurso r population s
give ris e t o particula r subpopulation s o f cell s only ;
(b) determine d b y a cloc k producin g a certai n cel l
type after a required number of precursor cell subdivisions
or with regard to some externally specified stage;
or (c) extrinsic, defined b y the externa l milieu of the
precursor cells , i n eithe r th e proliferativ e zone s o r
their eventual destination. The answe r that ma y vary
from on e brai n regio n t o anothe r i s likely th e usua l
developmental answer: all of the above. We give a few
specific examples , an d conside r th e implication s of
DEVELOPMENTAL DISORDERS AND EVOLUTIONARY EXPECTATIONS 11 3
hybrid mechanism s fo r producing norma l structure s
in response t o challenge.
In vivo and i n vitro experiments demonstrat e tha t
the order of neurogenesis and cell type are correlated .
For example, i n th e vertebrat e nervou s system, mos t
glia ar e produce d afte r th e completio n o f neurona l
generation (Ohnuma and Harris, 2003). In the retina,
the si x types of cells are produced i n order, although
in al l cases , th e productio n o f cel l type s overlap s
(Policy e t al, 1989) . Evidenc e suggest s that a com -
bination of clock-like initiation of specification o f particular
cel l type s an d feedbac k processes tha t asses s
how many cells of a class have been produced . On e
of these, p27 Ki P 1 , a cel l cycl e inhibitor, gradually increases
in progenitors until a critical level is reached,
whereupon cell s designate d a s oligodendrocytes exit
the cel l cycle and differentiat e (Freeman , 2000 ; Dyer
and Cepko , 2001 ; Ohnuma and Harris, 2003). Thus,
the gradua l accrual o f p27 Kl P 1 i s a negativ e feedbac k
mechanism tha t tells precursor cells when to start differentiating
into glia as opposed to neurons .
Injury i s capabl e o f resettin g th e neurogeneti c
mechanism. I n frog s an d fishes, for example, Mulle r
glia ca n re-ente r th e cel l cycl e i n respons e t o retinal
injury, an d ca n produc e progen y tha t differentiat e
into neurons (Reh and Levine, 1998) . In mature glia,
p2yKipi j s expresse d a t high levels . Following retinal
injury, however , p27 Klpl i s down-regulate d i n cells
that re-ente r th e cel l cycle , allowing for the genera -
tion o f ne w neurons . Regulatio n o f specificatio n of
cell classe s has als o been show n t o occu r a t a mor e
detailed level—fo r example , i f the retin a is depleted
of a particular class of amacrine cells while retinogenesis
is ongoing, the subsequent production of that cell
type is up-regulated (Reh, 1987) .
Negative feedback control of the rat e of histogenesis
provides flexibility and robustnes s in th e develop -
ing organis m relativ e t o mor e rigi d developmenta l
schemes tha t migh t plausibl y hav e evolved . Fo r in -
stance, suppos e tha t onl y gli a are produced o n a set
day following the onset of neuronogenesis, or that glia
are produce d onl y afte r a certain numbe r o f cell cy -
cles wit h n o feedbac k regulation . I n eithe r o f these
cases, if anything interferes with cel l productio n at a
certain tim e point , a n essentia l cel l grou p migh t
never be generated. On the other hand, if progression
through cel l classe s is regulated only by feedback, in
the cas e o f lo w resourc e availability , neurogenesis
could stal l at an earl y point an d neve r produce late -
generated cel l groups . Intrinsi c clocks , overlapping