Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons
Xiaolei Song1 • Haotian Chen1 • Zicong Shang1 • Heng Du1 • Zhenmeiyu Li1 • Yan Wen1 • Guoping Liu1 • Dashi Qi1 • Yan You1 • Zhengang Yang1 • Zhuangzhi Zhang1 • Zhejun Xu1
1 Institute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
Abstract
Medium spiny neurons (MSNs) in the striatum, which can be divided into D1 and D2 MSNs, originate from the lateral ganglionic eminence (LGE). Previously, we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs. Here, we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature. Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells. In addition, conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE. We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice. This suggests that, in the absence of Six3, abnormally differentiated D2 MSNs are eliminated by programmed cell death. These results further identify Six3 as an important regulatory element during D2 MSN differentiation.
Keywords
Six3; LGE; Drd2; striatum; Medium spiny neuron
