Previous studies of chimeric embryos suggest that huntingtin is required only in the extraembryonic tissue for proper development [16]. Signals from the extraembryonic tissue are critical for the induction of embryonic signals and for patterning the epiblast. Consequently, we examined extraembryonic development in huntingtin deficient embryos. Hnf4 is a transcription factor expressed in the primitive endoderm as soon as this tissue becomes distinct and is a key regulator of visceral endoderm secreted factors such as alphafetoprotein, apolipoproteins, and transferrin. Inactivation of Hnf4 results in impaired gastrulation [33,34]. At E7.5, Hnf4 is expressed in the columnar visceral endoderm cells at the extraembryonic-ectoderm junction (Fig. 4A, [33]). In Hdhex4/5/Hdhex4/5 embryos, consistent with normal primitive and visceral endoderm differentiation, Hnf4 expression appears normal, although the signal is stronger in mutant embryos compared to wild-type embryos (Fig. 4B). Similarly, Pem, a transcription factor expressed in proximal visceral endoderm and ectoplacental cone in wild-type embryos at E7.5, also is expressed in these tissues in the mutant embryos (Fig. 4C,D[35]). However, Pem expressing visceral endoderm hangs over the anterior of the mutant embryos, revealing abnormal location despite grossly normal differentiation.