Several underlying mechanisms could explain macrocephaly and minicolumn pathology, all based on altered embryonic cortical development (Figure 3). The first is an increase in the number of radial units in the embryonic cerebral cortex, which in turn is thought to depend upon an increase in the number of “founder” NSCs in the cortical primordium (Rakic, 1995) (Figure 3). This mechanism is supported by the occurrence of mutations in pten, a gene that regulates embryonic stem cell proliferation (Eng, 2003) in a small number of autistic patients with macrocephaly (Butler et al., 2005). Abnormal expression of this gene in NSCs would likely result in an intrinsic alteration of stem cells. Interestingly, an animal model of pten mutations shows increased brain size and social deficits (Kwon et al., 2006), although this mutation was in differentiated neurons, not intrinsically affecting NSCs. In Fragile X syndrome, which frequently presents with symptoms of autism, fetal NSCs have been shown to differentiate into neurons at greater rates (Castren et al., 2005) and to misexpress multiple genes involved in proliferation and differentiation (Bhattacharyya et al., 2008). Mutant embryonic NSCs isolated from mice lacking the fragile X mental retardation protein (FMRP) due to a deletion in the fmr1 gene differentiate in greater numbers into immature neurons (Castren et al., 2005). These findings are similar to those obtained in Drosophila germline stem cells lacking an ortholog of the fmr1 gene (Yang et al., 2009). Thus, the pten and fmr1 mouse models of ASD support the hypothesis that an intrinsic abnormality in NSC is responsible for features of these disorders. Two members of the TF-II family of transcription factors involved in Williams syndrome, another disorder with abnormal social behavior, have been shown in mice to regulate specific gene targets that may be involved in embryonic stem cell differentiation (Makeyev and Bayarsaihan, 2009).