Iniguez M A, De Lecea L, Guadano-Ferraz A, Morte B, Gerendasy D, Sutcliffe J G, Bernal J
Instituto de Investigaciones Biomedicas, Madrid, Spain.
Endocrinology. 1996 Mar;137(3):1032-41. doi: 10.1210/endo.137.3.8603571.
To identify thyroid hormone-sensitive neuronal populations in the forebrain, we studied the effects of thyroid hormone deficiency and replacement on the expression of RC3 messenger RNA (mRNA) in the rat brain by in situ hybridization. RC3/neurogranin is a brain-specific, calmodulin-binding, protein kinase C substrate that has been implicated in postsynaptic events involving calcium as a second messenger. We have previously shown that RC3 mRNA and protein concentrations are thyroid hormone dependent in developing and adult rats. In normal developing rats, RC3 expression occurs in two phases. Before postnatal day 10 (P10), RC3 mRNA was detected mainly in layers II/III and V of cerebral cortex and the CA fields of the hippocampus. From P10 to P15, it decreased in layer V and increased in layer VI, the retrosplenial cortex, the caudate-putamen nucleus, and the dentate gyrus. Expression in the caudate followed a lateral to medial gradient. Thyroid hormone deficiency interfered with the late phase of RC3 expression, such that developing hypothyroid rats showed lower RC3 expression in layer VI, the retrosplenial cortex, the dentate gyrus, and the caudate, and increased expression in layer V. These changes were reverted by T4 treatment. Adult- onset hyperthyroidism also reversibly decreased hybridization in the striatum. In contrast to other molecular targets of thyroid hormone in the brain, such as myelin genes, expression of RC3 was also affected by long term hypothyroidism in the absence of hormone replacement, indicating that thyroid hormone is a required factor for the cell-specific control of RC3 expression. In addition to identifying thyroid hormone-sensitive neurons, our results suggest that one action of thyroid hormone during brain development is the timely coordination of gene expression among phenotypically different, region-specific neuronal populations.
为了鉴定前脑中对甲状腺激素敏感的神经元群体，我们通过原位杂交研究了甲状腺激素缺乏和替代对大鼠脑中RC3信使核糖核酸（mRNA）表达的影响。RC3/神经颗粒蛋白是一种脑特异性、钙调蛋白结合、蛋白激酶C底物，它参与了以钙作为第二信使的突触后事件。我们之前已经表明，在发育中和成年大鼠中，RC3 mRNA和蛋白浓度依赖于甲状腺激素。在正常发育的大鼠中，RC3表达分两个阶段出现。在出生后第10天（P10）之前，RC3 mRNA主要在大脑皮层的II/III层和V层以及海马的CA区被检测到。从P10到P15，它在V层减少，在VI层、压后皮质、尾状壳核和齿状回增加。尾状核中的表达呈从外侧到内侧的梯度。甲状腺激素缺乏干扰了RC3表达的后期阶段，使得发育中的甲状腺功能减退大鼠在VI层、压后皮质、齿状回和尾状核中显示出较低的RC3表达，而在V层中表达增加。这些变化通过T4治疗得以逆转。成年期甲状腺功能亢进也可逆地降低纹状体中的杂交信号。与大脑中甲状腺激素的其他分子靶点（如髓磷脂基因）不同，在没有激素替代的情况下，长期甲状腺功能减退也会影响RC3的表达，这表明甲状腺激素是细胞特异性控制RC3表达所需的因素。除了鉴定对甲状腺激素敏感的神经元外，我们的结果还表明，甲状腺激素在大脑发育过程中的一个作用是及时协调表型不同、区域特异性神经元群体之间的基因表达。
