Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors

Irene Delgado,Miguel Torres,Jacques Drouin,Aurelio Balsalobre,Giovanna Giovinazzo,Susana Temiño,Yves Gauthier

doi:10.1038/s41467-021-23373-9

Abstract

Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.

Highlights

Meis[1] and Meis[2] are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins
The posterior region of limb buds displayed a sharp border of Hoxd[9] expression, producing a symmetrical expression domain along the AP axis. This can be observed by Hox[9] immunofluorescence (Fig. 7e, white arrowhead; N = 3/3). These results show that Meis is required for Shh activation through its role in regulating genes involved in AP limb prepatterning, including Gli[3], Hand[2], and 5′ Hoxd genes
We used a conditional targeting approach to study the effect of complete Meis loss-of-function on early limb bud development

Summary

Introduction

Meis[1] and Meis[2] are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; limb development in the complete absence of Meis function has not been studied. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. The main regulator of limb AP patterning is the secreted factor Shh, which is expressed from the zone of polarizing activity (ZPA), a discrete mesenchymal region at the posterior end of the limb bud[10,11]. We describe double Meis[1] and Meis[2] elimination in the limb-forming region and report Meis functions in limb induction and AP and PD patterning

Methods

Results

Conclusion