Moss Joanna J, Neal Chris R, Kague Erika, Lane Jon D, Hammond Chrissy L
School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK.
Wolfson Bioimaging Facility, Faculty of Life Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
Biol Open. 2025 Aug 15;14(8). doi: 10.1242/bio.062038. Epub 2025 Aug 19.
LMX1B, a LIM-homeodomain family transcription factor, plays critical roles in the development of multiple tissues, including limbs, eyes, kidneys, brain, and spinal cord. Mutations in the human LMX1B gene cause the rare autosomal-dominant disorder Nail-patella syndrome, which affects development of limbs, eyes, brain, and kidneys. In zebrafish, lmx1b has two paralogues: lmx1ba and lmx1bb. While lmx1b morpholino data exists, stable mutants were previously lacking. Here, we describe the characterisation of lmx1b stable mutant lines, with a focus on development of tissues that are affected in Nail-patella syndrome. We demonstrate that the lmx1b paralogues have divergent developmental roles in zebrafish, with lmx1ba affecting skeletal and neuronal development, and lmx1bb affecting renal development. The double mutant, representing loss of both paralogues (lmx1b dKO) showed a stronger phenotype, which included additional defects to trunk muscle patterning, and a failure to fully inflate the notochord leading to a dramatic reduction in body length. Overall, these mutant lines demonstrate the utility of zebrafish for modelling Nail-patella syndrome and describe a previously undescribed role for lmx1b in notochord cell inflation.
LMX1B是一种含LIM结构域的同源异型转录因子，在包括四肢、眼睛、肾脏、大脑和脊髓在内的多种组织发育中发挥关键作用。人类LMX1B基因突变会导致罕见的常染色体显性疾病——指甲-髌骨综合征，该疾病会影响四肢、眼睛、大脑和肾脏的发育。在斑马鱼中，lmx1b有两个旁系同源基因：lmx1ba和lmx1bb。虽然已有lmx1b吗啉代寡核苷酸的数据，但之前一直缺乏稳定的突变体。在此，我们描述了lmx1b稳定突变体系的特征，重点关注受指甲-髌骨综合征影响的组织的发育。我们证明，lmx1b的旁系同源基因在斑马鱼中具有不同的发育作用，lmx1ba影响骨骼和神经元发育，而lmx1bb影响肾脏发育。代表两个旁系同源基因均缺失的双突变体（lmx1b dKO）表现出更强的表型，包括躯干肌肉模式的额外缺陷，以及脊索未能完全膨胀导致体长显著缩短。总体而言，这些突变体系证明了斑马鱼在模拟指甲-髌骨综合征方面的实用性，并描述了lmx1b在脊索细胞膨胀中以前未被描述的作用。
