Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos

Itou, Junji; Kawakami, Hiroko; Quach, Thu; Osterwalder, Marco; Evans, Sylvia M.; Zeller, Rolf; Kawakami, Yasuhiko

doi:10.1242/dev.073056

Cited by 71 publications

(74 citation statements)

References 66 publications

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“…Isl1 was expressed in the ureteric mesenchyme surrounding the base of the ureteric bud stalk and the nephric duct in the wild-type kidneys ( Figure 4E; see also Figures 1 and 3A), which was abolished in the mutant kidneys ( Figure 4F). However, some mutant kidneys showed residual Isl1 expression, as evaluated by immunostaining, probably owing to the mosaic deletion of Hoxb6Cre as reported previously, 9 which could partly explain the variable kidney sizes at E14.5. If the kidney is formed to some extent, hydronephrosis and/or hydroureter could be a prominent phenotype owing to the obstruction at the ureterovesical junction.…”

Section: The Ureter Is Not Properly Connected To the Urinary Bladder supporting

confidence: 51%

Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Kaku¹,

Ohmori²,

Kudo³

et al. 2013

Journal of the American Society of Nephrology

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Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT. The mammalian kidney, the metanephros, is formed by reciprocally inductive interactions between two precursor tissues: the metanephric mesenchyme and the ureteric bud. The metanephric mesenchyme attracts the ureteric bud tips toward the mesenchyme and subsequently induces branching of the ureteric buds. The attracted ureteric bud tips in turn induce the mesenchymal cells to differentiate into the epithelia of the glomeruli and renal tubules. Impairment of these processes can lead to a variety of abnormal developmental disorders of the kidney. Meanwhile, the stalks of the ureteric buds elongate and differentiate into collecting ducts and the ureter. The ureteric epithelium also interacts with the surrounding ureteral mesenchyme, which differentiates into the smooth muscle layer of the ureter that pushes the urine downward by peristaltic movements. Therefore, mechanical obstruction of the ureter or malformation of the smooth muscle layer causes dilatation of the ureter (hydroureter) and, in more severe cases, of the renal pelvis (hydronephrosis). The combination of kidney and ureter defects caused by gene mutations is termed congenital anomalies of the kidney and urinary tract (CAKUT) and

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Section: The Ureter Is Not Properly Connected To the Urinary Bladder supporting

confidence: 51%

Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Kaku¹,

Ohmori²,

Kudo³

et al. 2013

Journal of the American Society of Nephrology

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“…The mouse lines for Sall4 (15,40), Gli3 (41), Tcre (21), Hoxb6Cre (22), and Prx1Cre (24) were maintained on a mixed genetic background. Skeletal preparation was done as published (42). Animal breeding and procedures were performed according to the approval by the Institutional Animal Care and Use Committee of the University of Minnesota.…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence of IRX3 (43) and SALL4 (Santa Cruz, sc-101147, 1/300 dilution) was performed on cryo-sections according to standard procedures (42). Simultaneous cell proliferation and cell death analyses were performed by using anti-phospho histone H3 (Upstate, catalog no.…”

Section: Methodsmentioning

confidence: 99%

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Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Akiyama

Kawakami

Wong

et al. 2015

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

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Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore-and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.Sall4 | Gli3 | limb progenitors | appendicular skeletal elements | Plzf-Hox H ow progenitor cells are spatially and temporarily organized to construct an organ is a central question in developmental biology. Limb skeletal elements develop from limb progenitors, which arise from the lateral plate mesoderm (LPM) that is originated from epithelial somatopleure (1). Limb progenitors initially form two paired protrusions, fore-and hindlimb buds, whose initiation occurs around embryonic day (E) 9.0 and E9.5, respectively, in mouse embryos. In the following steps, limb signaling centers, known as the zone of polarizing activity (ZPA) and apical ectodermal ridge (AER), are established. SHH (Sonic hedgehog) from the ZPA and FGF8 from the AER are major signal molecules that regulate proliferative expansion and patterning of early limb progenitor cells (reviewed in ref. 2). These processes lead to development of functional limbs with each skeletal element adopting a unique shape at a distinct location.Several studies suggest that limb progenitors consist of two distinct pools, an anterior progenitor pool and a posterior progenitor pool. The posterior progenitor pool consists of cells that once expressed Shh and cells that received paracrine effects of SHH, which contribute to digit 2 (d2), d3, d4, and d5 and the posterior zeugopod (ulna, fibula) (3-6). Contrary to this, the anterior ...

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“…None of the numerous combinations of posterior Hox loss-offunction mutants reported to date (9)(10)(11)(12)(13)(14) are known to lead to hindlimb AP patterning defects analogous to those reported for loss of Hox9 or Hox5 paralogs. Itou et al (53) recently demonstrated that LIM-homeodomain factor Islet1 is a critical regulator of Hand2 expression and the posterior compartment in hindlimbs. How the hindlimb anterior compartment is established remains to be discovered.…”

Section: Discussionmentioning

confidence: 99%

Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb

Hrycaj

McIntyre

et al. 2013

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

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To date, only the five most posterior groups of Hox genes, Hox9-Hox13, have demonstrated loss-of-function roles in limb patterning. Individual paralog groups control proximodistal patterning of the limb skeletal elements. Hox9 genes also initiate the onset of Hand2 expression in the posterior forelimb compartment, and collectively, the posterior HoxA/D genes maintain posterior Sonic Hedgehog (Shh) expression. Here we show that an anterior Hox paralog group, Hox5, is required for forelimb anterior patterning. Deletion of all three Hox5 genes (Hoxa5, Hoxb5, and Hoxc5) leads to anterior forelimb defects resulting from derepression of Shh expression. The phenotype requires the loss of all three Hox5 genes, demonstrating the high level of redundancy in this Hox paralogous group. Further analyses reveal that Hox5 interacts with promyelocytic leukemia zinc finger biochemically and genetically to restrict Shh expression. These findings, along with previous reports showing that point mutations in the Shh limb enhancer lead to similar anterior limb defects, highlight the importance of Shh repression for proper patterning of the vertebrate limb.

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Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos

Cited by 71 publications

References 66 publications

Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb

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