Transcriptomic Signature of Human Embryonic Thyroid Reveals Transition From Differentiation to Functional Maturation

Abstract

The human thyroid gland acquires a differentiation program as early as weeks 3–4 of embryonic development. The onset of functional differentiation, which manifests by the appearance of colloid in thyroid follicles, takes place during gestation weeks 10–11. By 12–13 weeks functional differentiation is accomplished and the thyroid is capable of producing thyroid hormones although at a low level. During maturation, thyroid hormones yield increases and physiological mechanisms of thyroid hormone synthesis regulation are established. In the present work we traced the process of thyroid functional differentiation and maturation in the course of human development by performing transcriptomic analysis of human thyroids covering the period of gestation weeks 7–11 and comparing it to adult human thyroid. We obtained specific transcriptomic signatures of embryonic and adult human thyroids by comparing them to non-thyroid tissues from human embryos and adults. We defined a non-TSH (thyroid stimulating hormone) dependent transition from differentiation to maturation of thyroid. The study also sought to shed light on possible factors that could replace TSH, which is absent in this window of gestational age, to trigger transition to the emergence of thyroid function. We propose a list of possible genes that may also be involved in abnormalities in thyroid differentiation and/or maturation, hence leading to congenital hypothyroidism. To our knowledge, this study represent the first transcriptomic analysis of human embryonic thyroid and its comparison to adult thyroid.

Modeling Human Thyroid Development by Fetal Tissue‐Derived Organoid Culture

“…[29] Transcriptomic signature comparison of human early embryonic thyroid and adult thyroid also identified cAMP signaling upregulation in adult thyroid. [11] Consistently, the dependence of adult TFC cells on the cAMP pathway has been reported by the latest study on adult mouse and human thyroid organoids. [30] However, when cAMP initiated in fetal thyroid and when subsequent cascade events occur in the narrow time window from thyroid organogenesis to functional maturation still remain elusive.…”

“…[ 7 , 9 ] In contrast, human studies only reported the expression pattern of specific genes in samples, [ 10 ] or the transcriptome of fetal thyroid at premature stage (7–11GWs). [ 11 ] The knowledge on the initiation of human fetal thyroid functional maturation at follicular growth stage is still limited. Recent single‐cell RNA sequencing (scRNA‐seq) of adolescent and adult zebrafish thyroid showed heterogeneity in developmental thyroid, [ 12 ] highlighting the potential of single‐cell molecular characterization in understanding thyroid maturation.…”

Thyroid hormone regulators in human cerebral cortex development

“…Taken together, the data show that the thyroid gland is already functional by GW11-12 (Dom et al 2021), shortly after the preplate splitting and the onset of cortical plate formation.…”

Foxe1 orchestrates thyroid and lung cell lineage divergence in mouse stem cell-derived organoids

“…In silico prediction of Foxe1 binding motifs in up-regulated genes at the level of RNA expression and chromatin accessibility revealed 107 potential targets of Foxe1, including Pax8 and Tg (Francis-Lang et al, 1992). Other targets identified included genes involved in proper thyroid function and TSH receptor activity or deregulated in thyroid cancer, such as Lrp2/Megalin (Marinò and McCluskey, 2000), DREAM/Kcnip3 (Andrea et al, 2005), Timp3 (Zarkesh et al, 2018), Slc26a7 (Dom et al, 2021) and Bcl-2 (Fagman et al, 2011; Porreca et al, 2012). Moreover, Foxe1 binding motifs were also found in genes related to the maintenance of follicle structure, the expression of various membrane-bound transporters, and the regulation of cell-matrix adhesion.…”