# Unraveling the Morphological and Functional Maturation Mechanisms Underlying Human Neural Development Using iPSCs‐Derived Neuronal Model

## TL;DR

This study uses a fast hiPSC-derived neuronal model to uncover key mechanisms in early human brain development.

## Contribution

A novel SMP protocol enables rapid neuronal maturation and identifies new roles for Cav1.2, Cav1.3, and ECEL1 in human neural development.

## Key findings

- Cav1.2 and Cav1.3 are essential for early human neuronal morphogenesis.
- ECEL1 regulates functional maturation through CALM3-mediated ion channel assembly.
- The SMP protocol creates a temporally compressed model of human neuronal development.

## Abstract

Emerging human induced pluripotent stem cells (hiPSCs)‐based neuronal models are useful for studying human neural development. However, existing protocols for differentiating neurons from hiPSCs generally require extended timeframes, making it difficult to capture the rapid, early stages of neuronal morphogenesis and functional maturation. This study presents an in vitro human neuronal model derived from hiPSCs with rapid morphological and functional maturity, by using the combined small molecules and proteins (SMP) protocol. This SMP‐induced, hiPSC‐derived neuronal model recapitulates core aspects of human neuronal development, providing a temporally compressed system for studying early neuronal development. On the basis of this model, this study demonstrates that both Cav1.2 and Cav1.3, the two subtypes of L‐type voltage‐gated calcium channels that mediate calcium ion influx, are essential for early morphogenesis of human neuronal development. Moreover, ECEL1 (endothelin converting enzyme‐like 1) is identified as a key regulator of human neuronal functional developmental maturation in the early stage of SMP‐induced hiPSCs differentiation. ECEL1 acts through calmodulin 3 (CALM3) to regulate functional assembly and expression of multiple ion channels (e.g., voltage‐gated sodium ion channels) in neuronal functional development and maturation. These findings illuminate novel mechanisms underlying the morphogenesis and functional maturation of human neurons that are involved in human brain development.

Using human induced pluripotent stem cells (hiPSCs)‐derived neuronal model, Tian and colleagues reveal that voltage‐gated calcium channels Cav1.2 and Cav1.3, and their mediated calcium ion influx, are essential for early morphogenesis of human neuronal development, while ECEL1 underlies human neuronal functional developmental maturation through CALM3‐mediated ion channels assembly in neuronal functional development.