Stottmann R W, Tran P V, Turbe-Doan A, Beier D R
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Dev Biol. 2009 Nov 1;335(1):166-78. doi: 10.1016/j.ydbio.2009.08.023. Epub 2009 Sep 2.
Organizing centers in the developing brain provide an assortment of instructive patterning cues, including Sonic hedgehog (Shh). Here we characterize the forebrain phenotype caused by loss of Ttc21b, a gene we identified in an ENU mutagenesis screen as a novel ciliary gene required for retrograde intraflagellar transport. The Ttc21b mutant has defects in limb, eye and, most dramatically, brain development. We show that Shh signaling is elevated in the rostral portion of the mutant embryo, including in a domain in or near the zona limitans intrathalamica. We demonstrate here that ciliary defects seen in the Ttc21b mutant extend to the embryonic brain, adding forebrain development to the spectrum of tissues affected by defects in ciliary physiology. We show that development of the Ttc21b brain phenotype is modified by lowering levels of the Shh ligand, supporting our hypothesis that the abnormal patterning is a consequence of elevated Shh signaling. Finally, we evaluate Wnt signaling but do not find evidence that this plays a role in causing the perturbed neurodevelopmental phenotype we describe.
发育中的大脑中的组织中心会提供一系列指导性的模式形成线索，包括音猬因子（Shh）。在此，我们描述了因Ttc21b缺失所导致的前脑表型，Ttc21b是我们在ENU诱变筛选中鉴定出的一个新的纤毛基因，是逆向纤毛内运输所必需的。Ttc21b突变体在四肢、眼睛，尤其是大脑发育方面存在缺陷。我们发现，在突变体胚胎的前部，包括丘脑间限制带内或其附近的一个区域，Shh信号增强。我们在此证明，Ttc21b突变体中出现的纤毛缺陷延伸至胚胎大脑，使前脑发育也被纳入受纤毛生理缺陷影响的组织范围。我们表明，通过降低Shh配体的水平可改变Ttc21b大脑表型的发育，这支持了我们的假设，即异常模式形成是Shh信号增强的结果。最后，我们评估了Wnt信号，但未发现其在导致我们所描述的神经发育表型紊乱中起作用的证据。
