The mouse Engrailed-1 gene and ventral limb patterning

Loomis, Cynthia A.; Harris, Elizabeth Ann; Michaud, Jacques L.; Wurst, Wolfgang; Hanks, Mark C.; Joyner, Alexandra L.

doi:10.1038/382360a0

Cited by 296 publications

(234 citation statements)

References 22 publications

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“…Further, En1 is not expressed in the ventral ectoderm, and the ventral mesenchyme of ␤-catenin mutants is dorsalized. These results support a model in which Bmp signaling is required for the establishment of En1 expression in the ventral ectoderm, which then restricts expression of Wnt7a to the dorsal ectoderm and Wnt7a-dependent activation of Lmx1b to the dorsal mesenchyme (Riddle et al 1995;Loomis et al 1996Loomis et al , 1998Ahn et al 2001;Pizette et al 2001). The loss of Bmp signaling has been reported to result in a failure in AER induction and Fgf8 expression, similar to the Wnt3/␤-catenin mutants (Ahn et al 2001;Pizette et al 2001 Our results provide strong genetic evidence that Wnt3/␤-catenin signaling is required in the ectoderm to establish and maintain the presence of the AER in the mouse.…”

Section: Establishment Of Dorsoventral Patterning In the Mouse Limbsupporting

confidence: 66%

EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

Barrow¹,

Thomas²,

et al. 2003

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The formation of the apical ectodermal ridge (AER) is critical for the distal outgrowth and patterning of the vertebrate limb. Recent work in the chick has demonstrated that interplay between the Wnt and Fgf signaling pathways is essential in the limb mesenchyme and ectoderm in the establishment and perhaps the maintenance of the AER. In the mouse, whereas a role for Fgfs for AER establishment and function has been clearly demonstrated, the role of Wnt/␤-catenin signaling, although known to be important, is obscure. In this study, we demonstrate that Wnt3, which is expressed ubiquitously throughout the limb ectoderm, is essential for normal limb development and plays a critical role in the establishment of the AER. We also show that the conditional removal of ␤-catenin in the ventral ectodermal cells is sufficient to elicit the mutant limb phenotype. In addition, removing ␤-catenin after the induction of the ridge results in the disappearance of the AER, demonstrating the requirement for continued ␤-catenin signaling for the maintenance of this structure. Finally, we demonstrate that Wnt/␤-catenin signaling lies upstream of the Bmp signaling pathway in establishment of the AER and regulation of the dorsoventral polarity of the limb. The formation of the apical ectodermal ridge (AER) has long been known to play a critical role in the distal outgrowth and patterning of the vertebrate limb. Classical experiments performed by Saunders (1948) demonstrated that surgical removal of this tissue shortly after its formation results in severe truncations of the entire limb, whereas removal at progressively later stages in development allows outgrowth of the more distal elements in a progressive fashion. Given the critical role that the AER plays in limb development, a major focus within the limb field has been to identify molecules that are involved in its establishment and maintenance. The result of this effort has been the discovery that several signaling pathways interact in the establishment of the AER. For example, recent work in the chick has demonstrated that cooperation between the Wnt/␤-catenin and Fgf signaling pathways is essential in establishing the AER. Briefly, the prevailing model is as follows: Wnt/␤-catenin signaling in the limb mesenchyme appears to be required to activate Fgf10 expression in the same tissue (Kawakami et al. 2001). Mesenchymally derived Fgf10 then regulates expression of Wnt3a in the overlying surface ectoderm and later in the subset of ectodermal cells that is destined to give rise to the AER (Kengaku et al. 1997(Kengaku et al. , 1998. Wnt3a signaling is then thought to act through the ␤-catenin pathway to activate the expression of Fgf8 in these pre-AER cells (Kengaku et al. 1998). Fgf8 signaling to the mesenchyme maintains Fgf10 expression, presumably through the mesenchymal Wnt/␤-catenin pathway, thereby completing a regulatory circuit that is critical for maintenance of the AER (see Kawakami et al. 2001).In the mouse, genetic evidence supports the involvement of both Fgf and Wnt/␤-c...

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Section: Establishment Of Dorsoventral Patterning In the Mouse Limbsupporting

confidence: 66%

EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

Barrow¹,

Thomas²,

et al. 2003

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“…3C). This difference is specific to the epidermis during the period when interfootpad appendages are forming and was not observed in forelimb tissues at earlier stages of limb development when En1 plays a role in dorsal ventral patterning (15) (Fig. 3C).…”

Section: Differential Cis-regulation Of En1 Underlies Expression Diffmentioning

confidence: 99%

“…As eccrine glands are exclusively found on the ventral surface of the limb, there is a consequent absence of eccrine glands in the dorsalized distal limb of En1 homozygous knockout mice (15). In their place are large, dorsal-type hair follicles in what would have been the ventral skin, as well as hyperpigmentation and hypoplasia of footpads, circumferential nails and dorsally patterned tendons and muscles (15). Thus, any direct effect on eccrine gland development in the homozygous knock-out is obscured by the general dorsalization of the skin.…”

Section: Differential Cis-regulation Of En1 Underlies Expression Diffmentioning

confidence: 99%

“…Augmented expression of the FVB/N En1 allele is therefore the result of cis-regulatory changes, as both alleles are exposed to the same transacting factors in the F1 skin, a finding consistent with the model that cis-regulatory differences at the En1 locus are responsible for the ectodermal appendage phenotypes mapped to Chr1. (15). As eccrine glands are exclusively found on the ventral surface of the limb, there is a consequent absence of eccrine glands in the dorsalized distal limb of En1 homozygous knockout mice (15).…”

Section: Differential Cis-regulation Of En1 Underlies Expression Diffmentioning

confidence: 99%

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A genetic basis of variation in eccrine sweat gland and hair follicle density

Kamberov

Karlsson

Kamberova

et al. 2015

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

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Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin's surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin.eccrine sweat gland | hair follicle | ectodermal placode | engrailed 1 | ectodermal appendage

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“…7 This finding highlights the importance of R-spondins in human development and adds to our understanding of the signaling pathways involved in the patterning of epidermal appendages. Other developmental signaling pathways, including Wnt and FGF, have been implicated in limb and digit formation, [8][9][10] but RSPO4 is the first molecule specifically playing a key role in nail development.…”

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confidence: 99%