Bosze Bernadett, Suarez-Navarro Julissa, Soofi Abdul, Lauderdale James D, Dressler Gregory R, Brown Nadean L
Department of Cell Biology & Human Anatomy, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
Dev Biol. 2021 Apr;472:18-29. doi: 10.1016/j.ydbio.2020.12.020. Epub 2021 Jan 9.
The vertebrate eye anlage grows out of the brain and folds into bilayered optic cups. The eye is patterned along multiple axes, precisely controlled by genetic programs, to delineate neural retina, pigment epithelium, and optic stalk tissues. Pax genes encode developmental regulators of key morphogenetic events, with Pax2 being essential for interpreting inductive signals, including in the eye. PAX2 mutations cause ocular coloboma, when the ventral optic fissure fails to close. Previous studies established that Pax2 is necessary for fissure closure and to maintain the neural retina -- glial optic stalk boundary. Using a Pax2 knock-in allele we discovered that the mutant optic nerve head (ONH) lacks molecular boundaries with the retina and RPE, rendering the ONH larger than normal. This was preceded by ventronasal cup mispatterning, a burst of overproliferation and followed by optic cup apoptosis. Our findings support the hypothesis that ONH cells are tripotential, requiring Pax2 to remain committed to glial fates. This work extends current models of ocular development, contributes to broader understanding of tissue boundary formation and informs the underlying mechanisms of human coloboma.
脊椎动物的眼原基从大脑长出并折叠成双层视杯。眼睛沿着多个轴形成模式，由遗传程序精确控制，以界定神经视网膜、色素上皮和视神经柄组织。Pax基因编码关键形态发生事件的发育调节因子，其中Pax2对于解读诱导信号至关重要，包括在眼睛中。PAX2突变会导致眼裂，此时视杯腹侧裂无法闭合。先前的研究表明，Pax2对于裂的闭合以及维持神经视网膜 - 胶质视神经柄边界是必需的。利用一个Pax2敲入等位基因，我们发现突变的视神经乳头（ONH）与视网膜和视网膜色素上皮（RPE）缺乏分子边界，使得ONH比正常的更大。在此之前是鼻腹侧视杯模式异常、一阵过度增殖，随后是视杯凋亡。我们的研究结果支持这样的假说，即ONH细胞具有三潜能性，需要Pax2来维持其胶质命运。这项工作扩展了当前的眼发育模型，有助于更广泛地理解组织边界形成，并为人类眼裂的潜在机制提供了信息。
