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Two Lmx1b-associated cis-regulatory modules (LARM1/2) mediate Lmx1b auto-amplification during limb dorsalization and their disruption can cause a limb-specific form of Nail-Patella syndrome

AuthorsOberg, Kerby C.; Haro, Endika ; Petit, Florence; Pira, Charmaine; Spady, Conor; Ivey, Lauren; Gray, Austin; Escande, Fabienne; Jourdain, Anne-Sophie; Nguyen, Andy; Good, Jean-Marc; Francannet, Christine; Manouvrier-Hanu, Sylvie; Ros, María A.
Issue Date2-Jul-2019
CitationLimb Development and Regeneration: New Tools for a Classic Model System EMBO Workshop (2019)
AbstractDuring limb development, the Lmx1b homeodomain transcription factor is restricted to dorsal mesenchyme and is required for distal dorsalization. Lmx1b also contributes to kidney, eye and cerebellar development. Haploinsufficiency of the human LMX1B genes causes Nail-Patella Syndrome (NPS) characterized by nail dysplasia, absent or hypoplastic patellae, eye abnormalities, and progressive kidney disease. In the functional Lmx1b knockout mouse, transcription of the mutant Lmx1b mRNA in the limb is reduced, indicating a role for Lmx1b in an auto-amplifying feedback loop. Previous Lmx1b-targeted ChIP-seq data identified two Lmx1b-associated regulatory modules (LARM1/2) bound by Lmx1b. Herein, we demonstrate that LARM1/2 activity overlaps Lmx1b expression in the dorsal limb mesoderm and is dependent on conserved Lmx1b binding sites for activity. We also demonstrate interaction between the LARM enhancers and the Lmx1b promoter. In addition, we performed a targeted CRISPR-Cas excision of the LARM1/2 region in mice; loss of LARM1/2 reduced the expression of Lmx1b in normal mice and generated a phenotype with nearly symmetrical ventral-ventral distal limbs. LARM1/2 loss was limb-specific and did not affect any other Lmx1b-related organs. We extended our investigation to humans with an NPS phenotype that lacked a variation within the LMX1B coding sequence. In two families with a limb-restricted phenotype, loss-of-function variations in the LARM region were identified. These data indicate that the limb-specific expression of Lmx1b is amplified through an auto-regulatory loop involving LARM1/2. Furthermore, disruption of LARM1/2 function can cause isolated limb malformations in mice and human NPS.
DescriptionTrabajo presentado en Limb Development and Regeneration: New Tools for a Classic Model System EMBO Workshop, celebrado en Barcelona (España) del 2 al 5 de julio de 2019.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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