Table 1. Examples of well-known genes and genetic loci implicated in ASDs and/or NDDs with reported effects on proliferation or differentiation in NSCs.
| Gene | Functional effect |
|---|---|
| FMR1 | Regulation of cell differentiation47, 48, 49, 50, 51 |
| MECP2 | Modulates the balance between proliferation and neural differentiation through the Notch signaling pathway52 |
| TSC1/2 | Mutations cause premature differentiation and impaired maturation of neural precursor cells during both embryonic and postnatal development53 |
| ADNP | Role in neuronal differentiation and maintenance54, 55 |
| DLL1 | Promotes neuronal differentiation in the telencephalon56 |
| CTNNB1 | Functions in the decision of precursors to proliferate or differentiate during mammalian neuronal development57 |
| SMARCC2 | Promotes indirect neurogenesis by increasing the pool of progenitors58 |
| TBR1 | Promotes neuronal differentiation59 |
| CDKL5 | Mutation blocks cell cycle and promotes differentiation in neurons60 |
| PTEN | Deletion causes neuroblast differentiation through mTORC161 |
| CHD8 | Negative regulator of the Wnt-β-catenin signaling pathway62 |
| ARID1B | Part of the SWI/SNF complex, a cell cycle control complex63 |
| POGZ | Regulation of mitosis and proliferation in neurons64, 65 |
| SUV420H1 | Promotes neuroectodermal differentiation66 |
| EIF4E | Suppresses a pro-neurogenic program in neural progenitor cells67 |
| SHANK3 | Mediates sustained MAPK and PI3K signaling68 |
| NRXN1 | Reduced expression alters neuron differentiation69 |
| NLGN4X | Reduced expression delays neurodevelopment70 |
| 16p11.2 CNV | Reciprocal deletion and duplication CNV implicated in macrocephaly and microcephaly, respectively.71 May be caused by MAPK3 dosage effects |
| 1q21.1 CNV | Reciprocal deletion and duplication CNV implicated in microcephaly and macrocephaly, respectively.72 May be caused by CHD1L and/or BCL9 dosage effects |
Abbreviations: ASD, autism spectrum disorder; CNV, copy number variant; NDD, neurodevelopmental disorder; NSC, neural stem cell.
Many genes on this list have several functions (for example, NRXN1, NLGN4X and SHANK3 in cell adhesion), and here we have purposely shown only those functions associated with cell proliferation and differentiation, providing evidence that it is this pathway that unifies genes and loci associated with NDDs important to behavior and cognition. Our model predicts that genes that function to promote differentiation will show increased markers (microRNA, messenger RNA, DNA methylation patterns) of proliferation under disease conditions, whereas those genes that function to repress differentiation or allow NSCs to proliferate, will show increased markers of differentiation under disease conditions.