Overexpression of thyroid hormone receptor alpha 1 during zebrafish embryogenesis disrupts hindbrain patterning and implicates retinoic acid receptors in the control of hox gene expression

Nuclear receptors play key roles in anterior/posterior (A/P) axis formation during vertebrate embryogenesis. Within this gene family, retinoic acid re ceptors and retinoic acid itself have profound influences on the establishm ent of the A/P axis. Thyroid hormone receptors are expressed during early p eriods of development, long before the establishment of the thyroid gland, and are able to interact with retinoic acid receptors. Here we examined the ability of the thyroid hormone receptor al to affect early embryonic devel opment by mRNA injection of either repressor or activator forms of the thyr oid hormone receptor. Overexpression of either the thyroid hormone receptor al or a constitutive repressor form, v-erbA, caused a swelling in the rost ral hindbrain. These defects were associated with disorganization and loss of rhombomere borders as well as an increase in the number of acetylcholine esterase positive cells. This phenotype correlated with a reduction in hox al expression during gastrulation. Furthermore, injection of either thyroid hormone receptor al or v-erbA mRNA repressed a reporter gene that containe d a retinoic acid response element, demonstrating the ability of the thyroi d hormone receptor al to repress retinoic acid signaling during gastrulatio n. In contrast, embryos treated with retinoic acid alone or embryos injecte d with thyroid hormone receptor al and treated with the thyroid hormone ana log TRIAC displayed a similar set of defects, including loss of the midbrai n-hindbrain border and severe disruption of the rostral hindbrain. These st udies support the involvement of retinoic acid and its receptors in the dir ect control of Hox gene expression and the early patterning of the zebrafis h central nervous system.