We describe here the functional analysis of the C. elegans LIM homeobox gene lim-6, the ortholog of the mammalian Lmx-1a and b genes that regulate limb, CNS, kidney and eye development. lim-6 is expressed in a small number of sensory-, inter- and motorneurons, in epithelial cells of the uterus and in the excretory system. Loss of lim-6 function affects late events in the differentiation of two classes of GABAergic motorneurons which control rhythmic enteric muscle contraction. lim-6 is required to specify the correct axon morphology of these neurons and also regulates expression of glutamic acid decarboxylase, the rate limiting enzyme of GABA synthesis in these neurons. Moreover, lim-6 gene activity and GABA signaling regulate neuroendocrine outputs of the nervous system. In the chemosensory system lim-6 regulates the asymmetric expression of a probable chemosensory receptor. lim-6 is also required in epithelial cells for uterine morphogenesis. We compare the function of lim-6 to those of other LIM homeobox genes in C. elegans and suggest that LIM homeobox genes share the common theme of controlling terminal neural differentiation steps that when disrupted lead to specific neuroanatomical and neural function defects.

Reference

Bargmann
C. I.
,
Horvitz
H. R.
(
1991
)
Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans.
Neuron
7
,
729
742
Bargmann
C. I.
,
Kaplan
J. M.
(
1998
)
Signal transduction in the Caenorhabditis elegans nervous system.
Ann. Rev. Neurosci
21
,
279
308
Basson
M.
,
Horvitz
H. R.
(
1996
)
The Caenorhabditis elegans gene sem-4 controls neuronal and mesodermal cell development and encodes a zinc finger protein.
Genes Dev
10
,
1953
1965
Benveniste
R. J.
,
Thor
S.
,
Thomas
J. B.
,
Taghert
P. H.
(
1998
)
Cell type-specific regulation of the Drosophila FMRF-NH2 neuropeptide gene by Apterous, a LIM homeodomain transcription factor.
Development
125
,
4757
4765
Bredt
D. S.
(
1998
)
Sorting out genes that regulate epithelial and neuronal polarity.
Cell
94
,
691
4
Chen
H.
,
Lun
Y.
,
Ovchinnikov
D.
,
Kokubo
H.
,
Oberg
K. C.
,
Pepicelli
C. V.
,
Gan
L.
,
Lee
B.
,
Johnson
R. L.
(
1998
)
Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome.
Nat. Genet
19
,
51
55
Chen
H.
,
Ovchinnikov
D.
,
Pressman
C. L.
,
Aulehla
A.
,
Lun
Y.
,
Johnson
R. L.
(
1998
)
Multiple calvarial defects in lmx1b mutant mice.
Dev. Genet
22
,
314
320
Coburn
C. M.
,
Bargmann
C. I.
(
1996
)
A putative cyclic nucleotide-gated channel is required for sensory development and function in C. elegans.
Neuron
17
,
695
706
Coburn
C. M.
,
Mori
I.
,
Ohshima
Y.
,
Bargmann
C. I.
(
1998
)
A cyclic nucleotide-gated channel inhibits sensory axon outgrowth in larval and adult Caenorhabditis elegans: a distinct pathway for maintenance of sensory axon structure.
Development
125
,
249
258
Dahm
L. M.
,
Landmesser
L. T.
(
1988
)
The regulation of intramuscular nerve branching during normal development and following activity blockade.
Dev. Biol
130
,
621
644
Dahm
L. M.
,
Landmesser
L. T.
(
1991
)
The regulation of synaptogenesis during normal development and following activity blockade.
J. Neurosci
11
,
238
255
Dawid
I. B.
,
Breen
J. J.
,
Toyama
R.
(
1998
)
LIM domains: multiple roles as adapters and functional modifiers in protein interactions.
Trends Genet
14
,
156
162
Dreyer
S. D.
,
Zhou
G.
,
Baldini
A.
,
Winterpacht
A.
,
Zabel
B.
,
Cole
W.
,
Johnson
R. L.
,
Lee
B.
(
1998
)
Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.
Nat. Genet
19
,
47
50
Duret
L.
,
Guex
N.
,
Peitsch
M. C.
,
Bairoch
A.
(
1998
)
New insulin-like proteins with atypical disulfide bond pattern characterized in Caenorhabditis elegans by comparative sequence analysis and homology modeling.
Genome Res
8
,
348
353
Freyd
G.
,
Kim
S. K.
,
Horvitz
H. R.
(
1990
)
Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11.
Nature
344
,
876
9
German
M. S.
,
Wang
J.
,
Chadwick
R. B.
,
Rutter
W. J.
(
1992
)
Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex.
Genes Dev
6
,
2165
2176
Granato
M.
,
Schnabel
H.
,
Schnabel
R.
(
1994
)
pha-1, a selectable marker for gene transfer in C. elegans.
Nucleic Acids Res
22
,
1762
3
Grider
J. R.
,
Makhlouf
G. M.
(
1992
)
Enteric GABA: mode of action and role in the regulation of the peristaltic reflex.
Am. J. Physiol
262
,
690
694
Gu
X. H.
,
Kurose
T.
,
Kato
S.
,
Masuda
K.
,
Tsuda
K.
,
Ishida
H.
,
Seino
Y.
(
1993
)
Suppressive effect of GABA on insulin secretion from the pancreatic beta-cells in the rat.
Life Sci
52
,
687
694
Hart
A. C.
,
Sims
S.
,
Kaplan
J. M.
(
1995
)
Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor.
Nature
378
,
82
85
Hobert
O.
,
D'Alberti
T.
,
Liu
Y.
,
Ruvkun
G.
(
1998
)
Control of neural development and function in a thermoregulatory network by the LIM homeobox gene lin-11.
J. Neurosci
18
,
2084
2096
Hobert
O.
,
Mori
I.
,
Yamashita
Y.
,
Honda
H.
,
Ohshima
Y.
,
Liu
Y.
,
Ruvkun
G.
(
1997
)
Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene.
Neuron
19
,
3453
3457
Iannotti
C. A.
,
Inoue
H.
,
Bernal
E.
,
Aoki
M.
,
Liu
L.
,
Donis-Keller
H.
,
German
M. S.
,
Permutt
M. A.
(
1997
).
Identification of a human LMX1 (LMX1.1)-related gene, LMX1.2: tissue-specific expression and linkage mapping on chromosome 9.
Genomics
46
,
520
524
Jansen
G.
,
Hazendonk
E.
,
Thijssen
K. L.
,
Plasterk
R. H.
(
1997
)
Reverse genetics by chemical mutagenesis in Caenorhabditis elegans.
Nat. Genet
17
,
119
121
Jessen
K. R.
,
Hills
J. M.
,
Saffrey
M. J.
(
1986
)
Immunohistochemical demonstration of GABAergic neurons in the enteric nervous system.
J. Neurosci
6
,
1628
1634
Jin
Y.
,
Hoskins
R.
,
Horvitz
H. R.
(
1994
)
Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein.
Nature
372
,
780
783
Kimura
K. D.
,
Tissenbaum
H. A.
,
Liu
Y.
,
Ruvkun
G.
(
1997
)
daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans [see comments].
Science
277
,
942
946
Liu
D. W.
,
Thomas
J. H.
(
1994
)
Regulation of a periodic motor program in C. elegans.
J. Neurosci
14
,
1953
1962
Lundgren
S. E.
,
Callahan
C. A.
,
Thor
S.
,
Thomas
J. B.
(
1995
)
Control of neuronal pathway selection by the Drosophila LIM homeodomain gene apterous.
Development
121
,
1769
1773
Matise
M. P.
,
Joyner
A. L.
(
1997
)
Expression patterns of developmental control genes in normal and Engrailed-1 mutant mouse spinal cord reveal early diversity in developing interneurons.
J. Neurosci
17
,
7805
7816
McIntire
S.L.
,
Garriga
G.
,
White
J.
,
Jacobson
D.
,
Horvitz
H.R.
(
1992
).
Genes necessary for directed axonal elongation or fasciculation in C.elegans.
Neuron
8
,
307
322
McIntire
S. L.
,
Jorgensen
E.
,
Horvitz
H. R.
(
1993
)
Genes required for GABA function in Caenorhabditis elegans [see comments].
Nature
364
,
334
337
McIntire
S. L.
,
Jorgensen
E.
,
Kaplan
J.
,
Horvitz
H. R.
(
1993
)
The GABAergic nervous system of Caenorhabditis elegans [see comments].
Nature
364
,
337
341
McIntire
S. L.
,
Reimer
R. J.
,
Schuske
K.
,
Edwards
R. H.
,
Jorgensen
E. M.
(
1997
)
Identification and characterization of the vesicular GABA transporter.
Nature
389
,
870
876
Miller
C.
,
Sassoon
D. A.
(
1998
)
Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract.
Development
125
,
3201
32311
Miller
D. M.
,
Shen
M. M.
,
Shamu
C. E.
,
Burglin
T. R.
,
Ruvkun
G.
,
Dubois
M. L.
,
Ghee
M.
,
Wilson
L.
(
1992
)
C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons.
Nature
355
,
841
845
Mori
I.
,
Ohshima
Y.
(
1995
)
Neural regulation of thermotaxis in Caenorhabditis elegans.
Nature
376
,
344
348
Nelson
F. K.
,
Albert
P. S.
,
Riddle
D. L.
(
1983
)
Fine structure of the Caenorhabditis elegans secretory-excretory system.
J. Ultrastruct. Res
82
,
156
171
Nelson
F. K.
,
Riddle
D. L.
(
1984
)
Functional study of the Caenorhabditis elegans secretory-excretory system using laser microsurgery.
J. Exp. Zool
231
,
45
56
Newman
A. P.
,
White
J. G.
,
Sternberg
P. W.
(
1996
)
Morphogenesis of the C. elegans hermaphrodite uterus.
Development
122
,
3617
3626
Ogg
S.
,
Paradis
S.
,
Gottlieb
S.
,
Patterson
G. I.
,
Lee
L.
,
Tissenbaum
H. A.
,
Ruvkun
G.
(
1997
)
The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans.
Nature
389
,
994
999
Pfaff
S. L.
,
Mendelsohn
M.
,
Stewart
C. L.
,
Edlund
T.
,
Jessell
T. M.
(
1996
)
Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.
Cell
84
,
309
320
Porter
F. D.
,
Drago
J.
,
Xu
Y.
,
Cheema
S. S.
,
Wassif
C.
,
Huang
S. P.
,
Lee
E.
,
Grinberg
A.
,
Massalas
J. S.
,
Bodine
D.
,
Alt
F.
,
Westphal
H.
(
1997
)
Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development.
Development
124
,
2935
2944
Ren
P.
,
Lim
C. S.
,
Johnsen
R.
,
Albert
P. S.
,
Pilgrim
D.
,
Riddle
D. L.
(
1996
)
Control of C. elegans larval development by neuronal expression of a TGF-beta homolog.
Science
274
,
1389
1391
Riddle
R. D.
,
Ensini
M.
,
Nelson
C.
,
Tsuchida
T.
,
Jessell
T. M.
,
Tabin
C.
(
1995
)
Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb.
Cell
83
,
631
640
Rongo
C.
,
Whitfield
C. W.
,
Rodal
A.
,
Kim
S. K.
,
Kaplan
J. M.
(
1998
)
LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia.
Cell
94
,
751
759
Ruvkun
G.
,
Hobert
O.
(
1998
)
The Taxonomy of Developmental Control in Caenorhabditis elegans.
Science
282
,
2033
2041
Sanders
K. M.
(
1996
)
A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.
Gastroenterology
111
,
492
515
Sawa
H.
,
Lobel
L.
,
Horvitz
H. R.
(
1996
)
The Caenorhabditis elegans gene lin-17, which is required for certain asymmetric cell divisions, encodes a putative seven-transmembrane protein similar to the Drosophila frizzled protein.
Genes Dev
10
,
2189
2197
Schinkmann
K.
,
Li
C.
(
1992
)
Localization of FMRFamide-like peptides in Caenorhabditis elegans.
J. Comp. Neurol
316
,
251
260
Sharma
K.
,
Sheng
H. Z.
,
Lettieri
K.
,
Li
H.
,
Karavanov
A.
,
Potter
S.
,
Westphal
H.
,
Pfaff
S. L.
(
1998
)
LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons.
Cell
95
,
817
828
Shatz
C. J.
,
Stryker
M. P.
(
1988
)
Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents.
Science
242
,
87
89
Sorenson
R. L.
,
Garry
D. G.
,
Brelje
T. C.
(
1991
)
Structural and functional considerations of GABA in islets of Langerhans, beta-cells and nerves.
Diabetes
40
,
1365
1374
Sulston
J. E.
(
1983
)
Neuronal cell lineages in the nematode Caenorhabditis elegans.
ColdSpring Harb. Symp. Quant. Biol
48
,
443
452
Thomas
J. H.
(
1990
)
Genetic analysis of defecation in Caenorhabditis elegans.
Genetics
124
,
855
872
Thor
S.
,
Thomas
J. B.
(
1997
)
The Drosophila islet gene governs axon pathfinding and neurotransmitter identity.
Neuron
18
,
397
409
Thor
S.
,
Andersson
S.G.E.
,
Tomlinson
A.
,
Thomas
J.B.
(
1999
)
A LIM-homeodomain combinatorial code for motor neuron pathway selection.
Nature
397
,
76
80
Tsuchida
T.
,
Ensini
M.
,
Morton
S. B.
,
Baldassare
M.
,
Edlund
T.
,
Jessell
T. M.
,
Pfaff
S. L.
(
1994
)
Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes [see comments].
Cell
79
,
957
970
Vogel
A.
,
Rodriguez
C.
,
Warnken
W.
,
Izpisua Belmonte
J. C.
(
1995
)
Dorsal cell fate specified by chick Lmx1 during vertebrate limb development [published erratum appears in Nature 1996 Feb 29;379(6568):848].
Nature
378
,
716
720
Wadsworth
W. G.
,
Bhatt
H.
,
Hedgecock
E. M.
(
1996
)
Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans.
Neuron
16
,
35
46
Way
J. C.
,
Chalfie
M.
(
1989
)
The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types.
Genes Dev
3
,
1823
33
Way
J. C.
,
Chalfie
M.
(
1988
)
mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans.
Cell
54
,
5
16
White
J. G.
,
Southgate
E.
,
Thomson
J. N.
(
1992
)
Mutations in the Caenorhabditis elegans unc-4 gene alter the synaptic input to ventral cord motor neurons.
Nature
355
,
838
41
White
J. G.
,
Southgate
E.
,
Thomson
J. N.
,
Brenner
S.
(
1986
)
The structure of the nervous system of the nematode Caenorhabditis elegans.
Phil. Trans. Royal Soc. London B
314
,
1
340
Yu
S.
,
Avery
L.
,
Baude
E.
,
Garbers
D. L.
(
1997
)
Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors.
Proc. Natl. Acad. Sci. USA
94
,
3384
7
Zhou
H. M.
,
Walthall
W. W.
(
1998
)
UNC-55, an orphan nuclearhormone receptor, orchestrates synaptic specificity among two classes of motor neurons in Caenorhabditis elegans.
J. Neurosci
18
,
10438
10444
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