The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival.

Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre–mediated Tmem2 knockout (Tmem2^CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2^CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2^CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process. Author summary: As a major component of the extracellular matrix, hyaluronan is particularly abundant in the extracellular matrix of embryonic tissues, where its expression is dynamically regulated during tissue morphogenetic processes. Tissue levels of hyaluronan are regulated not only by its synthesis but also by its degradation. Curiously, mice lacking known hyaluronidase molecules, including HYAL1 and HYAL2, exhibit minimal embryonic phenotypes. As a result, our understanding of the role of the catabolic aspect of hyaluronan metabolism in embryonic development is quite limited. Here, we show that TMEM2, a recently identified hyaluronidase that degrades hyaluronan on the cell surface, plays a critical role in the development of neural crest cells and their derivatives. Our analyses of Tmem2 conditional knockout mice, Tmem2 knock-in reporter mice, and in vitro cell cultures demonstrate that TMEM2 is essential for generating a tissue environment needed for efficient migration of neural crest cells from the neural tube. Our paper reveals for the first time that the degradation of hyaluronan plays a specific regulatory role in embryonic morphogenesis, and that dysregulation of hyaluronan degradation leads to severe developmental defects. [ABSTRACT FROM AUTHOR]