Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis.
Neuronal progenitor cell proliferation and their optimum number are indispensable for neurogenesis, which is determined by cell cycle length and cell cycle quitting rate of the dividing progenitors. These processes are tightly orchestrated by transcription factors like Tbr2, Pax6, and E2f-1. Radial glia and intermediate progenitor cells (IPC) through direct and indirect neurogenesis maintain surface area and neocortical thickness during development. Here we show that fetal neurogenesis is maternal thyroid hormone (MTH) dependent with differential effect on direct and indirect neurogenesis. MTH deficiency (MTHD) impairs direct neurogenesis through initial down-regulation of Pax6 and diminished progenitor pool with recovery even before the onset of fetal thyroid function (FTF). However, persistent decrease in Tbr2 positive IPCs, diminished NeuN positivity in layers I-III of neocortex, and reduced cortical thickness indicate a non-compensatory impairment in indirect neurogenesis. TH deficiency causes disrupted cell cycle kinetics and deranged neurogenesis. It specifically affects indirect neurogenesis governed by intermediate progenitor cells (IPCs). TH replacement in hypothyroid dams partially restored the rate of neurogenesis in the fetal neocortex. Taken together we describe a novel role of maternal TH in promoting IPCs derived neuronal differentiation in developing neo-cortex. We have also shown for the first time that ventricular zone progenitors are TH responsive as they express its receptor, TR alpha-1, transporters (MCT8) and deiodinases. This study highlights the importance of maternal thyroid hormone (TH) even before the start of the fetal thyroid function.
Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, UP India.
Vishwa
V
Mohan
Rohit A
RA
Sinha
Amrita
A
Pathak
Leena
L
Rastogi
Praveen
P
Kumar
Amit
A
Pal
Madan M
MM
Godbole
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019579:Neocortex / Q000196:embryology / Q000473:pathology*; D058953:Neural Stem Cells / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000172:deficiency*
D013963:Thyroid Hormones