| Summary: | Providing appropriate positional identity and patterning information to distinct rostrocaudal subpopulations of cranial neural crest cells (CNCCs) is central to vertebrate craniofacial morphogenesis. <i>Hox</i> genes are not expressed in frontonasal and first pharyngeal arch (PA1) CNCCs, whereas a single <i>Hox</i> gene, <i>Hoxa2</i>, is necessary to provide patterning information to second pharyngeal arch (PA2) CNCCs. In frog, chick and mouse embryos, ectopic expression of <i>Hoxa2</i> in <i>Hox</i>-negative CNCCs induced hypoplastic phenotypes of CNCC derivatives of variable severity, associated or not with homeotic transformation of a subset of PA1 structures into a PA2-like identity. Whether these different morphological outcomes are directly related to distinct <i>Hoxa2</i> overexpression levels is unknown. To address this issue, we selectively induced <i>Hoxa2</i> overexpression in mouse CNCCs, using a panel of mouse lines expressing different <i>Hoxa2</i> ectopic expression levels, including a newly generated <i>Hoxa2</i> knocked-in mouse line. While ectopic <i>Hoxa2</i> expression at only 60% of its physiological levels was sufficient for pinna duplication, ectopic <i>Hoxa2</i> expression at 100% of its normal level was required for complete homeotic repatterning of a subset of PA1 skeletal elements into a duplicated set of PA2-like elements. On the other hand, ectopic <i>Hoxa2</i> overexpression at non-physiological levels (200% of normal levels) led to an almost complete loss of craniofacial skeletal structures. Moreover, ectopic <i>Hoxa5</i> overexpression in CNCCs, while also resulting in severe craniofacial defects, did not induce homeotic changes of PA1-derived CNCCs, indicating <i>Hoxa2</i> specificity in repatterning a subset of <i>Hox</i>-negative CNCCs. These results reconcile some discrepancies in previously published experiments and indicate that distinct subpopulations of CNCCs are differentially sensitive to ectopic levels of <i>Hox</i> expression.
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