Pitx2, a bicoid-related homeobox gene, is involved in Rieger's syndrome and the left-right (L-R) asymmetrical pattern formation in body plan. In order to define the genomic structure and roles of Pitx2, we analyzed the genomic structure and generated Pitx2-deficient mice with the lacZ gene in the homeobox-containing exon of Pitx2. We were able to show that among three isoforms of Pitx2, Pitx2c shows asymmetrical expression whereas Pitx2a, Pitx2b and Pitx2c show symmetrical expression. In Pitx2(−)(/)(−) embryos there was an increase in mesodermal cells in the distal end of the left lateral body wall and an amnion continuous with the lateral body wall thickened in its mesodermal layer. These changes resulted in a failure of ventral body wall closure. In lung and heart in which Pitx2 is expressed asymmetrically, right pulmonary isomerism, atrioventricular canals with prominent swelling, and juxtaposition of the atrium were detected. The hearts failed to develop tricuspid and mitral valves and a common atrioventricular valve forms. Further, dysgenesis of the Pitx2(−)(/)(−) extraocular muscle and thickening of the mesothelial layer of cornea were observed in the ocular system where Pitx2 is expressed symmetrically, and these resulted in enophthalmos. The present study shows that Pitx2 expressed in various sites participates in morphogenesis through three types of actions: the involvement of asymmetric Pitx2 expression in the entire morphogenetic process of L-R asymmetric organs; the involvement of asymmetric Pitx2 expression in the regional morphogenesis of asymmetric organs; and finally the involvement of symmetric Pitx2 expression in the regional morphogenesis of symmetric organs.

Reference

Bellusci
S.
,
Grindley
J.
,
Emoto
H.
,
Itoh
N.
,
Hogan
B. L. M.
(
1997
)
Fibroblast growth factor 10 (FGF10) and branching morophogenesis in the embryonic mouse lung.
Development
124
,
4867
4878
Boer
P. H.
,
Potten
H.
,
Adra
C. N.
,
Jardine
K.
,
Mullhofer
G.
,
McBurney.
M. W.
(
1990
)
Polymorphisms in the coding and noncoding regions of murine Pgk-1 alles.
Biochem. Genet
28
,
299
308
Campione
M.
,
Steinbeisser
H.
,
Schweickert
A.
,
Deissler
K.
,
van Bebber
F.
,
Lowe
L. A.
,
Nowotschin
S.
,
Viebahn
C.
,
Haffter
P.
,
Kuehn
M. R.
,
Blum
M.
(
1999
)
The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping.
Development
126
,
1225
1234
Chiang
C.
,
Litingtung
Y.
,
Lee.
E.
,
Young
K. E.
,
Corden
J. L.
,
Westphal
H.
,
Beachy
P. A.
(
1996
)
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Nature
383
,
407
413
Eisenberg
L. M.
,
Markwald
R. R.
(
1995
)
Molecular regulation of atrioventricular valvuloseptal morphogenesis.
Cir. Res
77
,
1
6
Gage
P. J.
,
Camper
S. A.
(
1997
)
Pituitary homeobox 2, a novel member of the bicoid-related famoly of homeobox genes, is a potential regulator of anterior structure formation.
Hum. Mol. Genet
6
,
457
464
Hummel
K. P.
,
Chapman
D. B.
(
1959
)
Visceral inversion and assocoiated anomalies in the mouse.
J. Hered
50
,
9
13
Izraeli
S.
,
Lowe
L. A.
,
Bertness
V. L.
,
Good
D. J.
,
Dorward
D. W.
,
Kirsch
I. R.
,
Kuehn
M. R.
(
1999
)
The SIL gene is required for mouse embryonic axial development and let-right specification.
Nature
399
,
691
694
Jorgenson
R. J.
,
Levin
L. S.
,
Cross
H. E.
,
Yoder
F.
,
Kelly
T. E.
(
1978
)
The Rieger syndrome.
Am. J. Med. Gen
2
,
307
318
Kitamura
K.
,
Miura
H.
,
Yanazawa
M.
,
Miyashita
T.
,
Kato
K.
(
1997
).
Expression patterns of Brx1 (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear foramation.
Mech. Dev
67
,
83
96
Kulharya
A. S.
,
Mabbery
M.
,
Kukolich
M. K.
,
Day
D. W.
,
Schneider
N. R.
,
Wilson
G. N.
,
Tonk
V.
(
1995
).
Interstitial deletions 4q21.1q25 and 4q25q27:phenotypic variability and relation to Rieger anomaly.
Am. J. Med. Genet
55
,
165
170
Lamers
W. H.
,
Wessels
A.
,
Verbeek
F. J.
,
Moorman
A. F. M.
,
Viragh
S.
,
Wenink
A. C. G.
,
Gittenberger-de Groot
A.
,
Anderson
R. H.
(
1992
)
New findings concerning ventricular septation in the human heart.
Circulation
86
,
1194
1205
Lin
C. R.
,
Kioussi
C.
,
O'Connell
S.
,
Briata
P.
,
Szeto
D.
,
Liu
F.
,
Izpisua-Belmonte
J. C.
,
Rosenfeld
M. G.
(
1999
)
Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis.
Nature
401
,
279
282
Logan
M.
,
Pagan-Westphal
S. M.
,
Smith
D. M. Paganessi
,
Tabin
C. J.
(
1998
)
The transcription factor Pitx2 mediates situs-specific morphogenensis is response to left-right asymmteric signals.
Cell
94
,
307
317
Lu
M.-F.
,
Pressman
C.
,
Dyer
R.
,
Johnson
R. L.
,
Martin
J. F.
(
1999
)
Function of Rieger syndrome gene in left-right asymmetry and carniofacial development.
Nature
401
,
276
278
Meno
C.
,
Shimono
A.
,
Saijoh
Y.
,
Yashiro
K.
,
Mochida
K.
,
Ohishi
S.
,
Noji
S.
,
Kondoh
H.
,
Hamada
H.
(
1998
)
lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal.
Cell
94
,
287
297
Miller
S.
,
White
R. D.
(
1998
)
Right-left asymmetry of cell proliferation predominates in mouse embryos undergoing clockwise axial rotation.
Anat. Rec
250
,
103
108
Mucchielli
M.-L.
,
Marinez
S.
,
Pattyn
A.
,
Goridis
C.
,
Brunet
J.-F.
(
1996
)
Otlx2, an Otx-related homeobox gene expressed in the pituitary gland and in the restricted pattern in the forebrain.
Mol. Cell. Neurosci
8
,
258
271
Oh
S. P.
,
Li
E.
(
1997
)
The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.
Genes Dev
11
,
1812
1826
Piedra
M. E.
,
Icardo
J. M.
,
Albajar
M.
,
Rodoriguez-Rey
J. C.
,
Ros
M. A.
(
1998
)
Pitx2 participates in the late phase of the pathway controlling left-right asymmetry.
Cell
94
,
319
324
Ryan
A. K.
,
Blumberg
B.
,
Rodriguez-Esteban
C.
,
Yonetani-Tamura
S.
,
Tamura
K.
,
Tsukui
T.
,
de la Pena
J.
,
Sabbagh
W.
,
Greenwald
J.
,
Choe
S.
,
Norris
D. P.
,
Robertson
E. J.
,
Evans
R. M.
,
Rosenfeld
M. G.
,
Belmonte
J. C. I.
(
1998
)
Pitx2 determines left-right asymmetry of internal oragans in vertebrates.
Nature
394
,
545
551
Semina
E. V.
,
Reiter
R.
,
Leysens
N. J.
,
Alward
W. L. M.
,
Small
K. W.
,
Datson
N. A.
,
Siegel-Batelt
J.
,
Bierke-Nelson
D.
,
Bitoun
P.
,
Zabel
B. U.
,
Carey
J. C.
,
Murray
J. C.
(
1996
)
Cloning and characterization of a novel bicoid-related homeobox transcription factorgene, RIEG, involved in Rieger syndrome.
Nature Genet
14
,
392
399
Tajbakhsh
S.
,
Rocancourt
D.
,
Cossu
G.
,
Buckingham
M.
(
1997
)
Refinding the genetic hierarchies controlling skeletal myogenesis: Pax-3 and myf-5 act upstream of myoD.
Cell
89
,
127
138
Takeuchi
T.
,
Yamazaki
Y.
,
Katoh-Fukui
Y.
,
Tsuchiya
R.
,
Kondo
S.
,
Motoyama
J.
,
Higashinakagawa
T.
(
1995
)
Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation.
Genes Dev
9
,
1211
1222
Yoshioka
H.
,
Meno
C.
,
Koshiba
K.
,
Sugihara
M.
,
Itoh
H.
,
Ishimaru
Y.
,
Inoue.
T.
,
Ohuchi
H.
,
Semina
E. V.
,
Murray
J. C.
,
Hamada
H.
,
Noji
S.
(
1998
)
Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry.
Cell
94
,
299
305
This content is only available via PDF.