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Endocrinology Vol. 138, No. 8 3119-3124
Copyright © 1997 by The Endocrine Society

ARTICLES

Lack of Effect of Thyroid Hormone on Late Fetal Rat Brain Development1

Harold L. Schwartz, M. Elizabeth Ross and Jack H. Oppenheimer

Thyroid Research Unit, Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine (H.L.S., J.H.O.), Cell Biology and Neuroanatomy (H.L.S., J.H.O.), and Neurology (M.E.R.), University of Minnesota Medical School, Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: Jack H. Oppenheimer, M.D., University of Minnesota, Box 91-UMHC, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455. E-mail: oppen001{at}maroon.tc.umn.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Studies were undertaken to test whether alterations in fetal brain thyroid hormone levels during the final week of gestation can prematurely induce gene expression in brain or affect cerebellar morphogenesis. Pregnant dams were treated either by administration of 0.025% methimazole (MMI) in the drinking water from day 14 post conception (PC14) or administration of 2.5 mg T4/100 g BW on PC15. On PC21, treatment with MMI resulted in a 53% fall in fetal brain T3 levels and excess T4 resulted in a 2- to 3-fold increase to concentrations observed in adult brains. Neither excess nor reduced levels of T3 caused alterations in the expression of the myelin basic protein, Pcp-2 or calmodulin kinase IV genes. Cerebella of control brains showed early evidence of foliation and the presence of a several cell thick Purkinje cell layer and an external granule layer. No treatment induced effects were evident. Thus, at the late fetal stage in the rat, the developing brain appears to be unresponsive to thyroid hormone despite the presence of thyroid hormone receptors. We infer the presence of as yet unidentified factors that suppress precocious response to thyroid hormone or the absence of cofactors essential for such a response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ROLE OF thyroid hormone in mammalian brain differentiation is well documented (1, 2, 3, 4). The best defined animal model of thyroid hormone-dependent brain development is the neonatal rat. Thyroid hormone plays a critical role in various aspects of morphogenesis, regulation of specific gene expression, and development of learning and motor skills. Deficient cellular maturation in the cerebral cortex of hypothyroid rats is characterized by smaller neuronal cell bodies that are more tightly packed than those in euthyroid animals. The poor development of the neuropil in these animals is due to diminished axonal and dendritic outgrowth, elongation, and branching as well as reduced numbers of dendritic spines. Inadequate cellular differentiation results in markedly reduced synaptogenesis. Delayed proliferation and migration of granule cells and marked stunting of the development of Purkinje cells is evident in the hypothyroid rat cerebellum. Diminished myelination of neuronal axons is observed in both cerebral cortex and in cerebellum. These deficiencies of morphogenesis are presumably the basis of the failure of normal development of learning and motor skills in the hypothyroid animal.

Rat pups are born with a relatively undeveloped brain (4, 5). The well documented maturational effects of thyroid hormone in the rat occur in the early neonatal period. Many studies have characterized a critical period, the first 2–3 weeks of life, during which thyroid hormone is required for normal brain development (1, 6, 7, 8, 9, 10, 11). This period generally corresponds to the last trimester of human pregnancy. In both species, delay in instituting hormone replacement therapy results in permanent structural and functional impairment.

What is less clear is the role of thyroid hormone in regulating rat brain development during the intrauterine period. Although the major rise in serum and tissue T3 concentration occurs during the week after birth, both thyroid hormone (12, 13) and its specific nuclear receptors (14, 15) were demonstrated in brains of fetal rats. Ruiz de Ona et al. (16) also demonstrated the presence of increasing type II 5'-iodothyronine deiodinase activity in the fetal brain and showed that this activity is sensitive to regulation by thyroid hormone during late gestation. These findings led to the suggestion that thyroid hormone is necessary for normal brain development in the fetus as it is during the early postnatal period (12, 15, 17).

The precise mechanism by which thyroid hormone induces its effects in the developing brain is poorly understood. It is assumed that these effects are mediated via nuclear mechanisms. A fundamental understanding of thyroid hormone action in the developing brain requires an explanation of the temporal patterns of initiation and cessation of hormone action. Such temporal patterns are clearly important in ensuring that expression of target genes is coordinated with the overall pattern of brain development. In this connection, we were curious about the role of thyroid hormone levels in the initiation of these developmental changes. Two genes, myelin basic protein (MBP) and Purkinje cell protein-2 (Pcp-2) contain well defined thyroid hormone response elements (TREs) and were shown to be regulated by T3 in transfection assays (18, 19). Recently, another gene, calmodulin kinase IV (CamK IV) was shown to be responsive to T3 in primary cultures of rat brain cells (20). We examined the expression of these genes as well as the pattern of cerebellar morphogenesis in an effort to determine whether premature elevation of thyroid hormone levels in brain during late gestation would precociously trigger the developmental changes ordinarily produced by the hormone in the postnatal period. In addition, we tested whether a reduction in brain thyroid hormone levels would retard the prenatal developmental pattern.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Timed pregnant rats were purchased from Harlan, Inc. (Madison, WI). The day of appearance of sperm in the canal was taken as day 0 of embryonic age. Hypothyroidism was induced by administration of 0.025% methimazole (MMI) in the drinking water starting on day 14 post conception (PC14). Calvo et al. (21) showed that T3 concentrations in fetal brain could be efficiently manipulated by administration of T4 to the pregnant dam. T4 entering the fetus by transplacental transport is taken up by the brain and locally converted to T3 by the type II iodothyronine deiodinase. Increased T3 levels in the fetal brain were thus achieved by a single ip injection of T4, 2.5 mg/100 g BW, to the dams on PC15. The dose of T4 was calculated on the basis of our earlier studies (22) to maintain plasma T4 levels in the dam at least 10-fold above the normal for the 6-day period of the study. Control animals received injections of the vehicle, 0.03 M NaOH. All fetuses were taken for study on PC21, 1 day before the expected day of delivery. Dams were killed by exsanguination under ether anesthesia. Fetuses were killed by decapitation and blood collected from the trunk. Plasma from three to four fetuses was pooled for assay. Brains were quickly excised, pooled in pairs, and stored in liquid nitrogen. Animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals. These studies were approved by the Animal Care and Use Committee of the University of Minnesota.

Total RNA was extracted using the guanidine thiocyanate procedure previously described (23) and stored at -80 C in 0.1 x SET to reduce RNA degradation. The relative masses of messenger RNAs (mRNAs) of interest were determined by Northern blot analysis. Hybridizations were carried out overnight at 42 C with 2 x 106 cpm/ml random primer [32P]-labeled complementary DNA probes for MBP provided by Dr. Arthur Roach (California Institute of Technology), Purkinje cell protein-2 (Pcp-2), a gift of Dr. Harry Orr (University of Minnesota) and calmodulin kinase IV (CamK IV) received from Dr. Anthony Means (Duke University Medical Center). The hybridized blots were autoradiographed using Kodak XAR-5 film (Eastman Kodak Co., Rochester, NY).

Brains for histological study were fixed by transcardiac perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer. Whole brains were removed, hemisected, and postfixed in paraformaldehyde for 4 h at 4 C. Tissues were then dehydrated in serial alcohols for paraffin embedding by standard protocol. Serial sagittal sections of 7 µm were cut from each block and every third section was mounted on Vectabond (Vector Labs, Burlingame, CA) coated slides. Sections were then histochemically stained with hematoxylin and eosin.

Weighed portions of brain were extracted for measurement of T3 and T4 content as described by Morreale de Escobar et al. (17) with the modification that pooled aqueous samples were not further purified through resin columns. Recovery of extracted iodothyronine was generally 60–70%. Plasma and tissue T3 was assayed by the RIA method of Surks et al. (24). Plasma T4 concentrations were measured by the Abbott fluorescence polarization immunoassay in the Clinical laboratories of the University of Minnesota Hospital.

Total brain DNA was assayed by the Burton procedure as modified by Giles and Meyers (25), total RNA as described by Fleck and Munro (26), and total protein by the method of Lowry et al. (27).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Maternal plasma T4 and T3 concentrations, summarized in Table 1Go, were measured at the end of the study on day 21 post conception. Plasma T4 in the T4-treated dams was 23.4 ± 0.9 µg/dl, nine times the control value of 2.7 ± 0.3 µg/dl. Maternal plasma T3 concentrations were also significantly (P < 0.05) increased from 0.42 ± 0.13ng/ml to 2.85 ± 0.86 ng/ml, presumably the result of peripheral deiodination of the increased T4 levels. As expected, MMI treatment effectively reduced both plasma T4 and T3 levels.


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  		Table 1. Plasma T4 and T3 concentrations in treated dams

 
Plasma and brain T3 concentrations in the fetuses clearly reflected the treatment regimens (Table 2Go). Plasma T3 was one-third the normal concentration in the MMI-treated fetuses (0.03 ± 0.003ng/ml vs. 0.09 ± 0.01ng/ml) and increased by a factor of two (0.18 ± 0.02ng/ml) in fetuses of dams who received T4. The T3 concentration in brain in the T4-treated group of fetuses was raised to 1.24 ± 0.19 ng/g from 0.47 ± 0.03 ng/g in the control group. This is approximately the concentration measured in the brains of the normal dams (Table 2Go). A similar range of values for T3 in untreated adult rat brain was reported by others (17, 21). Concentrations of T3 in the MMI-treated group were half those in the control group. All differences from normal were statistically significant (P < 0.05).


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  		Table 2. Plasma and brain T3 concentrations in fetuses and adults

 
Fetal body weight appears to be sensitive to the treatments, whereas brain weight was not affected (Table 3Go). MMI treatment resulted in a 17% reduction in body weight and excess T4 in an 11% increase. Because brain weight was unchanged, the organ/body weight ratios were proportionally shifted in the inverse direction. Similarly, a lack of effect of T3 concentration on cellular proliferation and differentiation in brain at this stage of development was reflected in the absence of any difference among these groups in brain total DNA, total RNA or protein (Table 4Go).


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  		Table 3. Fetal body and brain weight

 

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  		Table 4. Effect of treatment on fetal brain DNA, RNA, and protein concentrations

 
We examined, by Northern analysis, the relative concentrations of two mRNAs, MBP and Pcp-2, that were shown to be direct targets of thyroid hormone action (18, 19). The ontogeny of their expression is clearly delayed in postnatal hypothyroid pups (28), and excess hormone is reported to accelerate expression of myelin basic protein (29, 30). They also represent genes that are specifically expressed in different cells, MBP in oligodendroglia (Fig. 1AGo) and Pcp-2 (Fig. 1BGo) in cerebellar Purkinje cells. Samples of RNA from the adult females were included to demonstrate the degree of change in gene expression seen during normal development. With overexposure of the gels, a weak signal could be detected for MBP in the fetal brains (Fig. 1AGo), whereas none was observed for Pcp-2 (Fig. 1BGo). Neither MBP nor Pcp-2 mRNA concentrations in fetal or adult brains were affected by altering brain T3 levels. The lack of effect of thyroid hormone on these genes in the adult brain was previously reported (28, 31).



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  		Figure 1. Northern blots of total RNA from fetal brains taken at day 21 post conception from pregnant dams treated as described in the legend to Table 1Go: A, MBP; B, Purkinje cell protein-2; and C, Calmodulin kinase IV. Each lane contains 10 µg of total RNA extracted from a pool of two brains. Total RNA from individual brains of treated adult dams were included to demonstrate the increase in expression of these genes observed in the mature organ.

 
Recent reports (20, 32) suggested that the CamK IV gene, expressed in various neuronal cell types in cerebrum and cerebellum at different stages of brain development, may also be regulated by thyroid hormone. In agreement with Sakami et al. (33), a weak signal was evident in the fetal samples and was increased in intensity in the adult brains (Fig. 1CGo). As with the other mRNAs tested, there was no evidence of any consistent effect of altered thyroid state in either the fetal or adult stages .

Cerebella of hypo and hyperthyroid fetuses were morphologically indistinguishable from age-matched euthyroid controls at PC21 (Figs. 2Go and 3Go). The several cell thick Purkinje cell layer (PCL), as well as the external granule layer (EGL) were apparent, as was the early appearance of cerebellar foliation. As in controls, cerebellar foliation was more advanced medially (Fig. 2Go) than laterally (Fig. 3Go) in the anlage of treated animals. There was no apparent difference in the thickness of the EGL, or degree of maturation of the internal granule layer, small cells emerging just below the PCL, which at this age is only starting to emerge. Similarly, the appearance of migrating cells through the molecular layer of the developing cerebellar cortex was equivalent in treated and control fetuses. Thus, at the late fetal stage the developing cerebellum appears to be resistant to reduced or excess thyroid hormone levels, without evidence of altered maturation of granule cells in particular. This is consistent with the lack of expression of mature neuronal and glial markers in T3-treated animals at PC21.



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  		Figure 2. Histological appearance of rat cerebellum at day 21 post conception. Shown are sagittal sections taken from approximately the same level in the medial cerebellum of rats treated with vehicle alone (A); thyroxine (B); or methimazole (C) as described in the Legend to Fig. 1Go. Following anesthetization, animals were individually perfused transcardially with 4% paraformaldehyde. Brains were removed and postfixed, dehydrated in serial alcohols, embedded in paraffin, and thin sections (7 µm) were cut before staining in hematoxylin and eosin. Arrows indicate the EGL and PCL. In all three treatment conditions, the stage of development and cytoarchitecture of the cerebellum are indistinguishable at this fetal stage. Foliation is well underway, with the major lobules already apparent. The EGL is well populated and granule neurons are just beginning to migrate from this secondary germinal zone to move passed Purkinje neurons and establish the internal granular layer. Magnification 4x. Size bar in A, 500 µm.

 


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  		Figure 3. Histological appearance of rat cerebellum at day 21 post conception. Shown are sagittal sections taken from approximately the same level in the lateral cerebellum of rats treated with vehicle alone (A); thyroxine (B); or methimazole (C) as described in the legend to Table 1Go. Sections were prepared as described in the legend to Fig. 2Go. Magnification 4x. Size bar in A, 500 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our studies were directed to the question of whether thyroid hormone alone, in the presence of its specific nuclear receptors, is sufficient to induce early expression of target genes in the fetal rat brain. The concept that a surge in T3 production plays a decisive role in initiating developmental processes has been accepted in the study of amphibian metamorphosis (34). Tadpoles continue to grow but fail to undergo metamorphic differentiation in the absence of thyroid hormone (35). Moreover, administration of thyroid hormone can induce precocious metamorphosis (36). In contrast, the results of the present study provide no evidence that an increase in the level of thyroid hormone in the fetal rat brain, even in the presence of specific receptors, is sufficient to initiate the developmental process.

We chose as endpoints of hormone response two genes known to be regulated by thyroid hormone in the postnatal period, MBP and Pcp-2 (28, 31). Functional thyroid hormone response elements are present in the promoter regions of myelin basic protein (18) and Pcp-2 (19), indicating these genes may be direct targets of thyroid hormone regulation. These genes, expressed in oligodendroglia and Purkinje cells, respectively, begin in normal rat pups to be expressed following birth and their mRNAs reach adult levels by about postnatal day 20. The presence of T3-nuclear receptors in both these cell types was demonstrated by Carlson et al. (37). In hypothyroid rat pups, there is a clear delay of 1–2 days in the onset of expression of these genes, and maximum mRNA levels are also attained later than in normal pups (28). Despite the presence of excess T3 in the brain for the last 6 days of gestation, we observed no precocious induction of expression of either gene. Fetal brain T3 levels in T4-treated fetuses were raised to those measured in adult brains. A similar rise in euthyroid pups during the postnatal period is responsible for the normal development of the brain, including increased expression of the Pcp-2 and MBP genes and the well-described T3-dependent morphological maturation of the cerebrum and cerebellum. A recent study by Krebs et al. (20) suggested that mRNA levels of the CamK IV gene are regulated by T3. They reported that the level of this mRNA and its protein product were induced by T3 in rat telencephalon cell cultures. Whether this involves direct interaction between the T3-thyroid hormone receptor complex and a T3-responsive element on this gene is unknown. Under any circumstance, we were unable to observe any hormonal effect on this gene during the prenatal period.

In addition to the lack of effect of thyroid hormone on gene expression, we also observed no differences in morphological development. Many reports have demonstrated the importance of thyroid hormone to the normal morphogenetic development of the brain (for reviews see Refs. 1, 3, 4, 38). Excess hormone in the neonatal period leads to an early decline in the rate of cell formation in the germinative zones of the brain, resulting in a deficit of cells in both forebrain and cerebellum. DNA content, a reflection of cell number, was unaltered by the presence of either excess or insufficient hormone. RNA and protein content, measures of cellular differentiation, similarly were normal. Of course, localized effects might not be sufficient to be reflected by these measurements in the whole brain.

In the cerebellum, neonatal hypothyroidism results in persistence of the EGL and slowed migration of granule cells into the internal granule layer. Conversely, hyperthyroidism is associated with accelerated maturation of cerebellar neonatal EGL cells with resultant premature withdrawal of cells from proliferation and reduced cell numbers overall (39, 40, 41). In contrast to these postnatal effects, the present results indicate that, at least in the fetal cerebellum, cells are not yet competent to respond to alterations in thyroid hormone levels, despite the presence of thyroid hormone receptors. This is consistent with the observations of Alder et al. (42) in which granule cells isolated from the embryonic rhombic lip were found to be incapable of differentiating into granule neurons until cocultured with EGL cells from the postnatal cerebellum. Hence, in the environment of the postnatal EGL an important change occurs in the ability of granule precursors to respond to external signals governing their proliferation and differentiation, and this apparently includes responses to thyroid hormone. Similarly, Barres et al. (43) have reported that OZ-A cells, the precursor cells that differentiate into oligodendroglia, are unresponsive to thyroid hormone. They found these cells must proceed through at least several cycles of mitotic division before they gain sensitivity to thyroid hormone.

Although it is difficult to simulate the integrated T3 occupancy of receptors in the fetal brain that is present in the postnatal rat, our results show that the levels of T3 attained at the end of the treatment period were similar to those achieved spontaneously in the postnatal brain. The dose of T4 administered was clearly sufficient to produce marked increases in maternal plasma hormone levels throughout the period of study. After 6 days, maternal plasma T4 and T3 were still approximately 9- and 7-fold, respectively, above the normal control levels. Presumably, concentrations of both hormones were even higher at earlier times following the injection of T4 (22). Fetal plasma T3, in contrast, was only twice the normal concentration likely a result of both limited transplacental passage and rapid placental clearance of T3 (44, 45). Although fetal plasma and brain T4 levels could not be measured by the assay available to us, they were obviously raised sufficiently in the fetuses of T4-treated dams to allow increased local production of T3 in the fetal brains. The level attained approximates that in normal adult brains and, we would assume, sufficient to produce the known postnatal effects of the hormone on brain differentiation in the early neonatal period.

The basis of the observed effect of altered thyroid state on fetal body weight is unclear. Calvo et al. (46) found no effect of either methimazole treatment or excess hormone on fetal body weight during the same period of late gestation as examined in our study. In contrast, others found in rats that maternal hypothyroidism causes reduced fetal body weight despite normally functioning fetal thyroid glands (17, 47, 48). Bonet and Hererra (48) and Porterfield and Hendrich (47) concluded this was not a direct effect of insufficient hormone in the fetus but more likely secondary to the maternal hypothyroidism. Further studies are required to clarify the basis of these differences.

The principal findings in the present studies are (1) that prenatal elevation of thyroid hormone fails to induce the expression of T3-sensitive genes or to accelerate cerebellar morphogenesis and (2) that methimazole-induced hypothyroidism fails to retard cerebellar development. We interpret the first of these observations to signify that target genes that respond in the postnatal state to thyroid hormone are not sensitive to the action of the hormone in the prenatal state. Further, because the reduction of thyroid hormone by methimazole fails to delay cerebellar development during the prenatal period, thyroid hormone may not be important in prenatal development of cerebellum.

It may be of interest to speculate on the mechanism that allows specific genes to respond to thyroid hormone in the postnatal but not in the prenatal state. Such an effect could be mediated by the absence of a positive cofactor, essential for thyroid hormone gene regulation. Alternatively, such a factor could function in a negative fashion to suppress gene regulation by thyroid hormone.

With regard to the first possibility, we previously speculated that the effects of thyroid hormone in the central nervous system are mediated specifically by the TRß1 receptor isoform (23). The level of this isoform in brain appears to be extremely low in the prenatal state (23, 49). However, shortly after birth there is a striking increase in TRß1, so that it accounts for about one-third of the total receptors in the adult brain (49). However, recent studies by Forrest et al. (50) have shown that mice in which the TRß gene has been deleted by homologous recombination show remarkably few neurological deficits . Moreover, recent studies in our laboratory with the TRß-null mouse revealed no difference in the ontogeny of expression of MBP or Pcp-2 mRNA when compared with the wild-type (51). These findings effectively eliminate the possibility that the delayed effect of T3 is due to the late appearance of TRß1.

More recent observations in our laboratory have raised the alternative possibility that prenatal effects of thyroid hormone are effectively blocked by coexisting suppressor proteins. These studies demonstrated the presence of nucleoproteins in brains of fetal rats that bind to an upstream region of the Pcp-2 gene encompassing the TRE. These proteins disappear in the postnatal state (52). Studies are currently in progress to determine the nature and function of these nucleoproteins.

Lastly, the findings reported in this communication emphasize the generalization that the presence of T3 and thyroid hormone receptors in a prenatal tissue does not establish a functional role for T3 in such tissue. Neither, of course, do our findings rule out such a role.


   Footnotes
 
1 This research was supported by NIH Grants RO1-DK 19812 (to J.H.O.) and NS-31318 (to M.E.R.). Back

Received March 7, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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