Formation of Proximal and Anterior Limb Skeleton Requires Early Function of Irx3 and Irx5 and Is Negatively Regulated by Shh Signaling

• Published in: Developmental cell Vol. 29; no. 2; pp. 233 - 240
• Main Authors: Li, Danyi, Sakuma, Rui, Vakili, Niki A., Mo, Rong, Puviindran, Vijitha, Deimling, Steven, Zhang, Xiaoyun, Hopyan, Sevan, Hui, Chi-chung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.04.2014
• Subjects: Animals; Body Patterning - physiology; Bone Development - physiology; Femur - embryology; Femur - physiology; Gene Expression Regulation, Developmental; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hindlimb - embryology; Hindlimb - physiology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Limb Buds - embryology; Limb Buds - metabolism; Mice; Mice, Knockout; Mutation; Signal Transduction - physiology; Tibia - embryology; Tibia - physiology; Toes - embryology; Toes - physiology; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2014.03.001

Limb skeletal pattern relies heavily on graded Sonic hedgehog (Shh) signaling. As a morphogen and growth cue, Shh regulates identities of posterior limb elements, including the ulna/fibula and digits 2 through 5. In contrast, proximal and anterior structures, including the humerus/femur, radius/tibia, and digit 1, are regarded as Shh independent, and mechanisms governing their specification are unclear. Here, we show that patterning of the proximal and anterior limb skeleton involves two phases. Irx3 and Irx5 (Irx3/5) are essential in the initiating limb bud to specify progenitors of the femur, tibia, and digit 1. However, these skeletal elements can be restored in Irx3/5 null mice when Shh signaling is diminished, indicating that Shh negatively regulates their formation after initiation. Our data provide genetic evidence supporting the concept of early specification and progressive determination of anterior limb pattern. [Display omitted] •Formation of the femur, tibia, and digit 1 in the mouse hindlimb requires Irx3/5•Irx3/5 regulate limb AP prepattern and promote anterior limb progenitors•Forelimb and hindlimb buds experience different levels of Shh signaling•Shh signaling negatively regulates formation of the femur, tibia, and digit 1 Li et al. show that the formation of proximal and anterior limb elements is regulated at the earliest stages of limb bud initiation by the transcription factors Irx3/5. The definition of early anterior limb identity by Irx3/5 is subsequently antagonized and refined by posteriorizing Shh morphogen signaling.