Expression of general transcription factor and co-activator TAF4 varies during development and in the processes of cell differentiation with suggested connection to neurodegenerative diseases. Here, we show that expression of TAF4 alternative splice variants is different in various regions of the human brain, substantiating the role of alternative splicing of TAF4 in the regulation of neural development and brain function. Most of the described splicing events affect the TAFH homology domain of TAF4 (hTAF4-TAFH). Besides, differentiated towards neural lineages, normal human neural progenitors (NHNPs) lose canonical full-length TAF4 isoform. To study the effects of hTAF4-TAFH splicing on neuronal differentiation, we used RNAi approach to target hTAF4-TAFH-encoding domain in NHNPs. Results show that inactivation of hTAF4-TAFH domain accelerates differentiation of human neural progenitor cells. Conversely, enhanced expression of TAF4 suppresses differentiation and keeps neural progenitor cells in a stem cell-like state. Finally, we provide data on the involvement of TP53 and noncanonical WNT signaling pathways in mediating effects of TAF4 on neuronal differentiation. Overall, our data suggest that specific isoforms of TAF4 may selectively and efficiently control neurogenesis.