A study led by Thomas Vierbuchen and colleagues demonstrates that three transcription factors—Ascl1, Brn2, and Myt11—can directly convert mouse fibroblasts into functional neurons. The researchers identified these factors through a screening process involving 19 candidate genes, ultimately narrowing down to the three most effective. The resulting induced neuronal (iN) cells exhibit neuronal-specific proteins, generate action potentials, and form functional synapses. These cells were derived from both embryonic and postnatal fibroblasts, showing the potential for direct reprogramming of somatic cells into neurons without passing through a pluripotent state. The study highlights the ability of these transcription factors to induce mature neuronal characteristics, with Ascl1 alone inducing immature features, while the combination of Ascl1, Brn2, and Myt11 leads to more mature neurons. The iN cells display functional membrane properties, including the ability to generate action potentials and respond to neurotransmitters like GABA. They also form synapses with other neurons and with astrocytes, indicating their functional integration into neural circuits. The efficiency of the conversion process was found to be relatively high, with conversion rates ranging from 1.8 to 7.7%. The study also shows that the iN cells can be derived from various cell types, including tail-tip fibroblasts, and that they exhibit excitatory properties, expressing markers of cortical neurons. The research suggests that these iN cells could be valuable for studying neural development, neurological diseases, and regenerative medicine due to their functional similarity to native neurons. The findings challenge previous assumptions about the irreversibility of cellular differentiation and suggest that direct reprogramming of somatic cells into neurons is possible. This method offers a promising alternative to traditional stem cell approaches, as it avoids the use of pluripotent stem cells and has the potential to generate patient-specific neurons for therapeutic applications. The study also raises questions about the molecular mechanisms underlying the conversion process and the potential for further refinement of the reprogramming factors to enhance efficiency and specificity.A study led by Thomas Vierbuchen and colleagues demonstrates that three transcription factors—Ascl1, Brn2, and Myt11—can directly convert mouse fibroblasts into functional neurons. The researchers identified these factors through a screening process involving 19 candidate genes, ultimately narrowing down to the three most effective. The resulting induced neuronal (iN) cells exhibit neuronal-specific proteins, generate action potentials, and form functional synapses. These cells were derived from both embryonic and postnatal fibroblasts, showing the potential for direct reprogramming of somatic cells into neurons without passing through a pluripotent state. The study highlights the ability of these transcription factors to induce mature neuronal characteristics, with Ascl1 alone inducing immature features, while the combination of Ascl1, Brn2, and Myt11 leads to more mature neurons. The iN cells display functional membrane properties, including the ability to generate action potentials and respond to neurotransmitters like GABA. They also form synapses with other neurons and with astrocytes, indicating their functional integration into neural circuits. The efficiency of the conversion process was found to be relatively high, with conversion rates ranging from 1.8 to 7.7%. The study also shows that the iN cells can be derived from various cell types, including tail-tip fibroblasts, and that they exhibit excitatory properties, expressing markers of cortical neurons. The research suggests that these iN cells could be valuable for studying neural development, neurological diseases, and regenerative medicine due to their functional similarity to native neurons. The findings challenge previous assumptions about the irreversibility of cellular differentiation and suggest that direct reprogramming of somatic cells into neurons is possible. This method offers a promising alternative to traditional stem cell approaches, as it avoids the use of pluripotent stem cells and has the potential to generate patient-specific neurons for therapeutic applications. The study also raises questions about the molecular mechanisms underlying the conversion process and the potential for further refinement of the reprogramming factors to enhance efficiency and specificity.