Significance Phosphatase and tensin homolog protein (PTEN) and fragile X mental retardation protein (FMRP) play a vital role in neuronal development and function. This work provides new evidence for the genetic interaction of Pten and Fmr1 in postnatal development of granule neurons and conserved mechanisms across evolution. The observed cellular phenotypic defects in Pten and Fmr1 knockout (KO) could be rectified and restored by heterozygosity of Pten in Fmr1 KO neurons. Additionally, increased expression of PTEN in background Fmr1 KO animals suggests that FMRP negatively regulates PTEN, and we propose that introducing a combination of genetic mutations may normalize structural aspects of neuronal morphology by balancing each other’s expression.