The mechanisms by which multipotent progenitor cells are directed to alternative cell identities during the histogenesis of the vertebrate central nervous system are likely to involve several different types of signaling systems. Recent evidence indicates that 9-cis retinoic acid, which acts through members of the steroid/thyroid superfamily of receptors, directs progenitor cells to the rod photoreceptor cell fate. We now report that another effector of this family of receptors, thyroid hormone, induces an increase in the number of cone photoreceptors that develop in embryonic rat retinal cultures, and that combinations of 9-cis retinoic acid and triiodothyronine cause isolated progenitor cells to differentiate as either rods or cones, depending on the relative concentrations of the ligands. These results implicate thyroid hormone in CNS cell fate determination, and suggest that different photoreceptor phenotypes may be modulated through the formation of thyroid/retinoid receptor heterodimers.

Altshuler
D. M.
,
Cepko
C. L.
(
1992
)
A temporally regulated, diffusible activity is required for rod photoreceptor development in vitro.
Development
114
,
947
957
Altshuler
D. M.
,
Lo Turco
J. J.
,
Rush
J.
,
Cepko
C.
(
1993
)
Taurine promotes the differentiation of a vertebrate retinal cell type in vitro.
Development
119
,
1317
1328
Anchan
R.
,
Reh
T. A.
,
Angello
J.
,
Balliet
A.
,
Walker
M.
(
1991
)
EGF and TGFstimulate retinal neuroepithelial cell proliferation in vitro.
Neuron
6
,
1
20
Bradley
D. J.
,
Towle
H. C.
,
Young
W. S.
3d
(
1992
)
Spatial and temporal expression of alpha-and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system.
J. Neurosci
12
,
2288
2302
Bugge
T. H.
,
Pohl
J.
,
Lonnoy
O.
,
Stunnenberg
H. G.
(
1992
)
RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors.
EMBO J
11
,
1409
1418
Diaz-Araya
C.
,
Provis
J. M.
(
1992
)
Evidence of photoreceptor migration during early foveal development: A quantitative analysis of human fetal retina.
Vis. Neurosci
8
,
505
514
Dizhoor
A. M.
,
Ray
S.
,
Kumar
S.
,
Spencer
M.
,
Brolley
D.
,
Walsh
K. A.
,
Philipov
P. P.
,
Hurley
J. B.
,
Stryer
L.
(
1991
)
Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase.
Science
251
,
915
918
Dolle
P.
,
Fraulob
V.
,
Kastner
P.
,
Chambon
P.
(
1994
)
Developmental expression of murine retinoid X receptor (RXR) genes.
Mech. Dev
45
,
91
104
Dolle
P.
,
Ruberte
E.
,
Leroy
P.
,
Morriss-Kay
G.
,
Chambon
P.
(
1990
)
Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis.
Development
110
,
1133
1151
Durand
B.
,
Saunders
M.
,
Leroy
P.
,
Leid
M.
,
Chambon
P.
(
1992
)
All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs.
Cell
71
,
73
85
Forrest
D.
,
Sjoberg
M.
,
Vennstrom
B.
(
1990
)
Contrasting developmental and tissue-specific expression of alpha and beta thyroid hormone receptor genes.
EMBO J
9
,
1519
1528
Gaur
V. P.
,
De Leeuw
A. M.
,
Milam
A. H.
,
Saari
J. C.
(
1990
)
Localization of cellular retinoic acid-binding protein to amacrine cells of rat retina.
Exp. Eye Res
50
,
505
511
Giguere
V.
,
Ong
E. S.
,
Segui
P.
,
Evans
R. M.
(
1987
)
Identification of a receptor for the morphogen retinoic acid.
Nature
330
,
624
629
Gould
E.
,
Butcher
L. L.
(
1989
)
Developing cholinergic basal forebrain neurons are sensitive to thyroid hormone.
J. Neurosci
9
,
3347
3358
Hargrave
P.A.
,
McDowell
J.H.
(
1992
)
Rhodopsin and phototransduction.
Int. Rev. Cytol
137
,
49
97
Harris
W. A.
,
Messersmith
S. L.
(
1992
)
Two cellular inductions involved in photoreceptor determination in the Xenopus retina.
Neuron
9
,
357
372
Hendrickson
A.
(
1992
)
A morphological comparison of foveal development in man and monkey.
Eye
6
,
136
144
Hendrickson
A. E.
,
Kupfer
C.
(
1976
)
The histogenesis of the fovea in the macaque monkey.
Invest. Ophthalmol
15
,
746
756
Hetzel
B. S.
,
Chavadej
J.
,
Potter
B. J.
(
1988
)
The brain in iodine deficiency.
Neuropath. Appl. Neurobiol
14
,
93
104
Hicks
D.
,
Courtois
Y.
(
1992
)
Fibroblast growth factor stimulates photoreceptor differentiation in vitro.
J. Neurosci
12
,
2022
2033
Kelley
M. W.
,
Turner
J. K.
,
Reh
T. A.
(
1994
)
Retinoic acid promotes differentiation of photoreceptors in vitro.
Development
120
,
2091
2102
Kelley
M. W.
,
Turner
J. K.
,
Reh
T. A.
(
1995
)
Regulation of proliferation and photoreceptor differentiation in fetal human retinal cell cultures.
Invest. Ophthalmol. Vis. Sci
36
,
1280
1289
Kliewer
S. A.
,
Umesono
K.
,
Heyman
R. A.
,
Mangelsdorf
D. J.
,
Dyck
J. A.
,
Evans
R. M.
(
1992
)
Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling.
Proc. Natl. Acad. Sci. USA
89
,
1448
1452
Lauder
J. M.
(
1977
)
The effects of early hypo-and hyperthyroidism on the development of rat cerebellar cortex. III. Kinetics of cell proliferation in the external granular layer.
Brain Res
126
,
31
51
Leid
M.
,
Kastner
P.
,
Lyons
R.
,
Nakshatri
H.
,
Saunders
M.
,
Zacharewski
T.
,
Chen
J. Y.
,
Staub
A.
,
Garnier
J. M.
,
Mader
S.
, et al. 
(
1992
)
Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently.
Cell
68
,
377
395
Lerea
C.L.
,
Bunt-Milam
A.H.
,
Hurley
J.B.
(
1989
)
Alpha transducin is present in blue-, green-, and red-sensitive cone photoreceptors in the human retina.
Neuron
3
,
367
376
McCaffery
P.
,
Lee
M. O.
,
Wagner
M. A.
,
Sladek
N. E.
,
Drager
U. C.
(
1992
)
Asymmetrical retinoic acid synthesis in the dorsoventral axis of the retina.
Development
115
,
371
382
McCaffery
P.
,
Posch
K. C.
,
Napoli
J. L.
,
Gudas
L.
,
Drager
U. C.
(
1993
)
Changing patterns of the retinoic acid system in developing retina.
Dev. Biol
158
,
390
399
Mangelsdorf
D. J.
,
Borgmeyer
U.
,
Heyman
R. A.
,
Zhou
J. Y.
,
Ong
E. S.
,
Oro
A. E.
,
Kakizuka
A.
,
Evans
R. M.
(
1992
)
Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
Genes and Develop
6
,
329
344
Mangelsdorf
D. J.
,
Ong
E. S.
,
Dyck
J. A.
,
Evans
R. M.
(
1990
)
Nuclear receptor that identifies a novel retinoic acid response pathway.
Nature
345
,
224
229
Marks
M. S.
,
Hallenbeck
P. L.
,
Nagata
T.
,
Segars
J. H.
,
Appella
E.
,
Nikodem
V. M.
,
Ozato
K.
(
1992
)
H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes.
EMBO J
11
,
1419
1435
Marsh-Armstrong
N.
,
McCaffery
P.
,
Gilbert
W.
,
Dowling
J. E.
,
Drager
U. C.
(
1994
)
Retinoic acid is necessary for development of the ventral retina in zebrafish.
Proc. Natl. Acad. Sci. USA
91
,
7286
7290
Mellstrom
B.
,
Naranjo
J. R.
,
Santos
A.
,
Gonzalez
A. M.
,
Bernal
J.
(
1991
)
Independent expression of the alpha and beta c-erbA genes in developing rat brain.
Mol. Endocrinol
5
,
1339
1350
Milam
A. H.
,
Dacey
D. M.
,
Dizhoor
A. M.
(
1993
)
Recoverin immunoreactivity in mammalian cone bipolar cells.
Vis. Neurosci
10
,
1
12
Mlodzik
M.
,
Hiromi
Y.
,
Weber
U.
,
Goodman
C. S.
,
Rubin
G.
(
1990
)
The Drosophila seven-up gene, a member of the steroid receptor gene superfamily, controls photoreceptor cell fate.
Cell
60
,
211
224
Nicholson
J. L.
,
Altman
J.
(
1972
)
The effects of early hypo-and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation.
Brain Res
44
,
13
23
Packer
O.
,
Hendrickson
A. E.
,
Curcio
C. A.
(
1990
)
Developmental redistribution of photoreceptors across the Macaca nemestrina (pigtail macaque) retina.
J. Comp. Neurol
298
,
472
493
Petkovich
M.
,
Brand
N. J.
,
Krust
A.
,
Chambon
P.
(
1987
)
A human retinoic acid receptor which belongs to the family of nuclear receptors.
Nature
330
,
444
450
Pickard
M. R.
,
Sinha
A. K.
,
Ogilvie
L.
,
Ekins
R. P.
(
1993
)
The influence of the maternal thyroid hormone environment during pregnancy on the ontogenesis of brain and placental ornithine decarboxylase activity in the rat.
J. Endocrinol
139
,
205
212
Prati
M.
,
Calvo
R.
,
Morreale
G.
,
Morreale-de-Escobar
G.
(
1992
)
L-thyroxine and 3,5,3-triiodothyronine concentrations in the chicken egg and in the embryo before and after the onset of thyroid function.
Endocrinology
130
,
2651
2659
Raymond
P. A.
,
Reifler
M. J.
,
Rivlin
P. K.
(
1988
)
Regeneration of goldfish retina: rod precursors are a likely source of regenerated cells.
J. Neurobiol
19
,
431
463
Reh
T. A.
(
1987
)
Cell-specific regulation of neuronal production in the larval frog retina.
J. Neurosci
7
,
3317
3324
Reh
T. A.
(
1992
)
Cellular interactions determine neuronal phenotypes in rodent retinal cultures.
J. Neurobiol
23
,
1067
1083
Ruberte
E.
,
Dolle
P.
,
Chambon
P.
,
Morriss-Kay
G.
(
1991
)
Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos.
Development
111
,
45
60
Seleiro
E. A.
,
Darling
D.
,
Brickell
P. M.
(
1994
)
The chicken retinoid-X-receptor-gamma gene gives rise to two distinct species of mRNA with different patterns of expression.
Biochem. J
301
,
283
288
Sjoberg
M.
,
Vennstrom
B.
,
Forrest
D.
(
1992
)
Thyroid hormone receptors in chick retinal development: differential expression of mRNAs for alpha and N-terminal variant beta receptors.
Development
114
,
39
47
Sparrow
J. R.
,
Hicks
D.
,
Barnstable
C. J.
(
1990
)
Cell commitment and differentiation in explants of embryonic rat neural retina. Comparison with the developmental potential of dissociated retina.
Brain Res. Dev. Brain Res
51
,
69
84
Studer
M.
,
Popperl
H.
,
Marshall
H.
,
Kuroiwa
A.
,
Krumlauf
R.
(
1994
)
Role of a conserved retinoic acid response element in rhombomere restriction of Hoxb-1.
Science
265
,
1728
1732
Takumi
K.
,
Uehara
F.
(
1991
)
In vivo lectin-binding of photoreceptors and interphotoreceptor matrix in rat.
Jpn. J. Ophthalmol
35
,
16
22
Tsai
S.
,
Bartelmez
S.
,
Heyman
R.
,
Damm
K.
,
Evans
R.
,
Collins
S. J.
(
1992
)
A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line.
Genes Dev
6
,
2258
2269
Vandaele
S.
,
Nordquist
D. T.
,
Feddersen
R. M.
,
Tretjakoff
I.
,
Peterson
A. C.
,
Orr
H. T.
(
1991
)
Purkinje cell protein-2 regulatory regions and transgene expression in cerebellar compartments.
Genes Dev
5
,
1136
48
Watanabe
T.
,
Raff
M. C.
(
1992
)
Diffusible rod-promoting signals in the developing rat retina.
Development
114
,
899
906
Wikler
K. C.
,
Rakic
P.
(
1991
)
Relation of an array of early-differentiating cones to the photoreceptor mosaic in the primate retina.
Nature
351
,
397
400
Yip
D. K.
,
Auersperg
N.
(
1972
)
The dye-exclusion test for cell viability: persistence of differential staining following fixation.
In Vitro
7
,
323
329
Yu
V. C.
,
Delsert
C.
,
Andersen
B.
,
Holloway
J. M.
,
Devary
O. V.
,
Naar
A. M.
,
Kim
S. Y.
,
Boutin
J. M.
,
Glass
C. K.
,
Rosenfeld
M. G.
(
1991
)
RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements.
Cell
67
,
1251
1266
Yuodelis
C.
,
Hendrickson
A. E.
(
1986
)
A qualitative and quantitative analysis of the human fovea during development.
Vision Res
26
,
847
856
Zhang
X. K.
,
Hoffmann
B.
,
Tran
P. B.
,
Graupner
G.
,
Pfahl
M.
(
1992
)
Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors.
Nature
355
,
441
446
This content is only available via PDF.