Functional ablation of the mouse<i>Ldb1</i>gene results in severe patterning defects during gastrulation

Mukhopadhyay, Mahua; Teufel, Andreas; Yamashita, Tsuyoshi; Agulnick, Alan D.; Chen, Lan; Downs, Karen M.; Schindler, Alice B.; Grinberg, Alexander; Huang, Sing-Ping; Dorward, David W.; Westphal, Heiner

doi:10.1242/dev.00225

Cited by 132 publications

(154 citation statements)

References 77 publications

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“…The Ldb1-associated module behaves as the intramodule hub in the head organizer based on the properties of the protein products that constitute this complex. This notion is supported by the individual knockouts of Otx2, Lim1, Ldb1, and Ssdp1 genes: mutant embryos display a similar headless phenotype (5,17,(20)(21)(22)28).…”

Section: Resultsmentioning

confidence: 90%

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The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

Enkhmandakh

Makeyev²,

Bayarsaihan³

2006

Proc. Natl. Acad. Sci. U.S.A.

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Lim1, Ssdp1, and Ldb1 proteins are components of the Ldb1-associated transcriptional complex, which is important in the head-organizing activity during early mouse development. Depletion of each individual protein alone causes a headless phenotype. To explore in more detail the modular architecture of the complex, we have generated two different gene-trapped mouse lines that express truncated forms of Ssdp1. Embryos derived from the gene-trapped line that encodes a truncated Ssdp1 lacking the proline-rich sequence exhibit a lethal abnormal head-development phenotype, resembling mouse embryos deficient for Lim1, Ssdp1, or Otx2 genes. Embryos derived from the second gene-trapped line, in which most of the proline-rich domain of Ssdp1 is retained, did not show abnormalities in head development. Our data demonstrate that components of the Ldb1-dependent module can be subdivided further into discrete functional domains and that the proline-rich stretch of Ssdp1 is critical for embryonic head development. Furthermore, phylogenetic comparisons revealed that in Caenorhabditis elegans, a similar proline-rich sequence is absent in Ssdp but present in Ldb1. We conclude that although the overall architecture of the Ldb1-dependent module has been preserved, the genetic specification of its individual components has diversified during evolution, without compromising the function of the module.gene trap ͉ Ldb1 ͉ module

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Section: Resultsmentioning

confidence: 90%

“…According to the role of Ldb1 as a central core for multiple complexes in many developing structures, Ldb1 Ϫ/Ϫ embryos do not survive beyond embryonic day 9.5 because of pleiotropic abnormalities, including forebrain truncations (17). Lim1 is peripheral to Ldb1, and it is expected to show more local effects.…”

mentioning

confidence: 99%

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

Enkhmandakh

Makeyev²,

Bayarsaihan³

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Ldb1 is associated with the absence of PGCs (Mukhopadhyay et al, 2003). Ldb1 might, therefore, have a role in PGC formation independent of Lhx1 activity.…”

Section: Developmental Dynamicsmentioning

confidence: 96%

“…The difference between Lhx1 and Ldb1 function might be related to the effect of BMP signaling, which is known to be essential for the induction of PGC precursors. Bmp4 is down-regulated in the Ldb1-null mutant (Mukhopadhyay et al, 2003), but is still expressed in the extraembryonic tissues of the Lhx1-null embryo (Kinder et al, 2001). …”

Section: Developmental Dynamicsmentioning

confidence: 99%

Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse

Tanaka

Yamaguchi

Steiner

et al. 2010

Developmental Dynamics

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Mouse embryos lacking Lhx1 (Lim1) activity display defective gastrulation and are deficient of primordial germ cells (PGCs) (Tsang et al. [2001] International Journal of Developmental Biology 45:549–555). To dissect the specific role of Lhx1 in germ cell development, we studied embryos with conditional inactivation of Lhx1 activity in epiblast derivatives, which, in contrast to completely null embryos, develop normally through gastrulation before manifesting a head truncation phenotype. Initially, PGCs are localized properly to the definitive endoderm of the posterior gut in the conditional mutant embryos, but they depart from the embryonic gut prematurely. The early exit of PGCs from the gut is accompanied by the failure to maintain a strong expression of Ifitm1 in the mesoderm enveloping the gut, which may mediate the repulsive activity that facilitates the retention of PGCs in the hindgut during early organogenesis. Lhx1 therefore may influence the localization of PGCs by modulating Ifitm1‐mediated repulsive activity. Developmental Dynamics 239:2851–2859, 2010. © 2010 Wiley‐Liss, Inc.

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“…Homozygous Ldb1 knockout mice die mid gestation (E9.5-E10) with numerous defects, including a lack of blood cells; this phenomenon is thought to indicate an essential role for Ldb1 in Lmo2-containing transcriptional complexes in the yolk sac. 19 Although the LIM1 domain from Lmo2 appears to be the primary determinant of Ldb1-binding activity, both LIM domains are required for high affinity binding. 16,20,21 Recombinant forms of Lmo2 tend to be insoluble, but it is possible to overcome this problem by creating fusion proteins in which either or both of the LIM domains are tethered to Ldb1 LID via a flexible linker.…”

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confidence: 99%

Solution structure of a tethered Lmo2_LIM2/Ldb1_LID complex

Dastmalchi¹,

Wilkinson-White²,

Kwan³

et al. 2012

Protein Science

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LIM-only protein 2, Lmo2, is a regulatory protein that is essential for hematopoietic development and inappropriate overexpression of Lmo2 in T-cells contributes to T-cell leukemia. It exerts its functions by mediating protein-protein interactions and nucleating multicomponent transcriptional complexes. Lmo2 interacts with LIM domain binding protein 1 (Ldb1) through the tandem LIM domains of Lmo2 and the LIM interaction domain (LID) of Ldb1. Here, we present the solution structure of the LIM2 domain of Lmo2 bound to Ldb1 LID . The ordered regions of Ldb1 in this complex correspond well with binding hotspots previously defined by mutagenic studies. Comparisons of this Lmo2 LIM2 -Ldb1 LID structure with previously determined structures of the Lmo2/Ldb1 LID complexes lead to the conclusion that modular binding of tandem LIM domains in Lmo2 to tandem linear motifs in Ldb1 is accompanied by several disorder-to-order transitions and/ or conformational changes in both proteins.

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Functional ablation of the mouseLdb1gene results in severe patterning defects during gastrulation

Cited by 132 publications

References 77 publications

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse

Solution structure of a tethered Lmo2_LIM2/Ldb1_LID complex

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Functional ablation of the mouseLdb1gene results in severe patterning defects during gastrulation

Cited by 132 publications

References 77 publications

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

The role of the proline-rich domain of Ssdp1 in the modular architecture of the vertebrate head organizer

Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse

Solution structure of a tethered Lmo2LIM2/Ldb1LID complex

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Solution structure of a tethered Lmo2_LIM2/Ldb1_LID complex