Requirement of the MASH‐1 transcription factor for neuroendocrine differentiation of thyroid C cells

Abstract

Thyroid C cells are neural crest-derived neuroendocrine cells that can acquire features similar to serotonergic neurons. Based on developmental and phenotypic markers, we have previously proposed that C cells and serotonergic enteric neurons arise from a common sympathoadrenal progenitor. In this report, we genetically examined this relationship using mice lacking the mammalian achaete-scute homologue 1 (MASH-1) transcription factor, since MASH-1 has recently been shown to be required for differentiation of serotonergic enteric neurons. We found that MASH-1 knockout mice have a greatly reduced number of C cells based on the lack of calcitonin and serotonin immunoreactivity. In contrast, calcitonin and serotonin were still expressed in cultured mature C cells that no longer express MASH-1, demonstrating that MASH-1 is not directly required for the expression of these two markers. Hence, MASH-1 is required to establish the C-cell phenotype and supports the model that C cells lie in the neuronal differentiation pathway of the sympathoadrenal neural crest.

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

“…However, both of these two hASH1 þ adenocarcinomas also expressed neuroendocrine markers. Thus, our data confirmed and extended the findings of previous in vitro studies that hASH1 was specifically expressed in lung cancers with neuroendocrine differentiation, 12,14,18,19 indicating that besides being instrumental in development of a subset of neurons and neuroendocrine cells, 8,[13][14][15][16][17] hASH1 also plays a key role in regulating neuroendocrine differentiation of tumor cells. The term 'neuroendocrine differentiation' in a broad sense is used to define cells expressing a neural and/or an endocrine phenotype.…”

“…This work was supported by Grants from the Ministry of Education, Culture, Sports, Science and Technology (15590314 and High-tech research center) and from the Ministry of Health, Labor and Welfare (11)(12)(13)(14)(15)(16)(17)(18)(19) 2002), Japan…”

“…8,13 MASH1 is also indispensable for the development of pulmonary neuroendocrine cells, thyroid C cells and adrenal chromaffin cells in fetal mice, and homozygous MASH1 null mice lack pulmonary neuroendocrine cells, while mice deficient in HES1, a specific repressor gene of hASH1, show a marked increase in pulmonary neuroendocrine cells. [14][15][16][17] In vitro studies also documented restrictive hASH1 expression in tumor cell lines with neuroendocrine or neuronal differentiation such as pulmonary small-cell carcinoma, medullary thyroid carcinoma and neuroblastoma, 12,14,[18][19][20][21][22][23] suggesting a key role for hASH1 in dictating cellular neuroendocrine differentiation in lung cancer. However, few data about in vivo hASH1 expression in lung cancer, as well as in other neuroendocrine tumors, are currently available.…”

A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype

“…Another transcription factor in the list, Hes-related with YRPW motif 1 (Hey1), also maintains the neural precursor phenotype in brain: it negatively regulates basic helix-loop-helix (bHLH) transcription factors, such as mouse achaete scute homolog 1 (mAsh1) and mouse atonal homolog 3 (Math3) that induce neuronal differentiation (40). (The bHLH transcription factor mAsh1 is essential for differentiation of NE cell lineages; mAsh1 Ϫ/Ϫ mice die at birth and lack NE cells in their lungs and thyroid (41)(42)(43)). Thus, the induction of Sox2 and Hey1 as pPCs transdifferentiate to NE-like iGCs may be important in maintaining their relatively undifferentiated͞invasive growth properties.…”

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

“…However, Mash1 is essential for the differentiation of neuroendocrine cells in the lung, the adrenal gland, the thyroid, and is thus an important factor regulating endocrine development in another context (Ball, 2004, Huber et al, 2002, Lanigan et al, 1998. Interestingly, differentiation and survival of the mouse olfactory epithelium depends on Mash1 function comparable to that of Ascl1a in zebrafish pituitary development (Guillemot et al, 1993).…”