Huntington's disease is a neurological disorder caused by an expansion of CAG repeats in the huntingtin gene (HTT). Symptoms of Huntington's disease typically develop in adults but, in recent years, scientists have found a developmental component to this disorder. Now, Ali Brivanlou and colleagues identify a role for HTT and CAG expansion in gastrulation. Using CRISPR/Cas9, the authors generate human embryonic stem cells (hESCs) with expanded CAG repeats and analyse the ability of these cells to form germ layers in a 2D gastruloid model. These 2D gastruloids form upon treatment of hESCs with BMP4, which induces Wnt expression and activates activin/Nodal signalling. In colonies formed from hESCs with expanded CAG repeats, the ectodermal layer is reduced and there is an accompanying enlargement of the endodermal layer. In wild-type gastruloids, SMAD2 signalling (which is activated by activin) is restricted to outer cells during germ layer formation, but in cells with expanded CAG repeats the signal spreads towards the centre of the colony. The authors find that the failure to restrict SMAD2 signalling is due to the inability of cells with 56+ CAG repeats to respond to activin in a polarised fashion; this is caused by mislocalisation of TGFβ receptors on their apical surface. Together, these data demonstrate a role for HTT in gastrulation and provide a possible link between the developmental phenotype and the neurodegeneration observed with the onset of classic symptoms.
