Decoding Cell Fate: How Scalloped and Nerfin-1 Team Up in Neurons

Samir D’Costa in Science & Nature September 2025 • 5 min read.

"Unraveling the roles of Scalloped and Nerfin-1 transcription factors in maintaining neuronal cell fate: A new understanding of neurological health and disease."

For years, scientists believed that once a cell specialized, it was locked into that identity forever. However, pioneering research has revealed that cell differentiation is far more flexible. It's now clear that cells can actually reverse their specialization, a process called 'dedifferentiation'. This can be problematic in conditions like cancer, where cells lose their normal function and start dividing uncontrollably. Understanding how cells maintain their specialized roles is therefore critical to understanding and treating disease. This understanding not only sheds light on disease mechanisms but also paves the way for innovative approaches in regenerative medicine, offering hope for repairing damaged tissues and organs.

The intricate process of creating a nervous system has many parallels across species. By studying the relatively simple nervous system of the fruit fly, Drosophila melanogaster, scientists have uncovered fundamental principles that apply to human brain development. In the fruit fly's central nervous system (CNS), neural stem cells divide asymmetrically, giving rise to daughter cells that become specialized neurons or glial cells. How neurons maintain their specialized function after they're created has remained a key question. Recent work suggests that 'dedifferentiation' involves changes in how genes are expressed, indicating that transcription factors—proteins that control gene activity—play a crucial role in maintaining a neuron's identity.

In the fruit fly brain, two transcription factors, Nerfin-1 and Lola, have been shown to be essential for maintaining neuronal cell fate. When these proteins are lost, neurons revert to a stem cell-like state. New research is pinpointing how Nerfin-1 works to maintain a neuron's specialized function by activating specific neuronal genes and repressing genes linked to proliferation and stem cell identity. This study identifies a new partner for Nerfin-1, a protein called Scalloped (Sd), and explores how these two transcription factors cooperate to ensure neurons maintain their identity in the fruit fly brain.

How Do Scalloped and Nerfin-1 Work Together to Maintain Neuronal Identity?

To investigate how Nerfin-1 controls neuron fate, researchers focused on its potential interaction with Scalloped (Sd), a key transcription factor involved in the Hippo signaling pathway. The Hippo pathway is known for its role in controlling organ size, but Sd also collaborates with other proteins to regulate development in various cell types. The study highlights that the orthologs of Sd and Nerfin-1, namely EGL-44 and EGL-46, interact physically and coordinate the regulation of specific cell fates, such as that of the FLP cell, and cell cycle exit of Q neuroblasts in C. elegans. Additionally, TEAD1 and INSM1, the mammalian orthologs, are crucial in controlling pancreatic neuroendocrine cell identity.

What Are the Implications of These Findings?

This research highlights the importance of transcription factor partnerships in maintaining cell identity and preventing dedifferentiation. By working together, Sd and Nerfin-1 ensure that medulla neurons retain their specialized function. Disrupting this partnership leads to a reversion to a more stem cell-like state, potentially contributing to neurological disorders or tumor formation. Future research will focus on identifying the specific genes regulated by the Sd/Nerfin-1 complex and how this regulation prevents dedifferentiation. Understanding these mechanisms could lead to new strategies for treating neurological diseases, promoting brain repair, and preventing cancer development.