Orderly specification and precise laminar deployment of mouse cortical projection neuron types through intermediate progenitors

Dhananjay Huilgol, Jesse M. Levine, William Galbavy, Bor-Shuen Wang, and Z. Josh Huang. Developmental Cell, 21 July 2025. https://doi.org/10.1016/j.devcel.2025.02.009

-IP가 운명 결정된 세포로서 특정 뉴런 유형을 생산하고 이를 정밀하게 층별로 배치한다는 핵심 발견을 직관적으로 보여주는 대표 이미지임.

Abstract:

The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis (dNG) or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the ‘‘inside-out’’ model, whereby successive generations of PNs sequentially migrate first to deep and then progressively to more superficial layers. However, its biological significance remains unclear, and the role of iNG in this process is unknown. Using genetic strategies linking PN birth dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviates from a stringent inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams.

한글 초록 요약본:

마우스 대뇌피질에서 서로 다른 투사 뉴런 (pyramidal projection neuron, PN) 유형들이 중간 전구 세포 (intermediate progenitors, IPs)를 통해 어떻게 시간적으로 정렬되고 층별로 정확히 배치되는지를 연구함. 연구진은 Tbr2+ IPs가 여러 유형의 뉴런을 생성할 수 있다는 점을 주목하고, 이들이 각기 다른 유전자 발현 프로그램을 통해 뉴런의 정체성과 층별 위치를 정밀하게 결정한다는 사실을 밝혔음.

한글 논문 요약본 (Intro, Methods, Results)

1) Introduction: 대뇌피질의 뉴런들은 발생 중 정해진 층에 배치되고, 고유한 기능을 가지며 연결망을 형성함. 이러한 뉴런들은 신경 줄기세포에서 유래되며 중간 전구 세포 (IPs)를 거쳐 최종적으로 특화된 뉴런이 됨. IPs는 과거에는 단순히 뉴런 수를 늘리는 중간 단계로만 여겨졌으나, 최근에는 특정한 운명을 유도할 수 있음이 제기됨. 본 연구는 Tbr2 유전자를 활용한 유전학적 계통 추적 (fate mapping)기법으로, IPs가 생성하는 PN의 유형, 생성 시점, 층별 위치 및 투사 경로를 세포 분열 주기 수준에서 정밀하게 추적하고자 함.

2) Methods

l  Tbr2-2A-CreER 마우스 모델을 이용해 IP를 시간 특이적으로 표지.

l  Tamoxifen 유도, MADM/ Ai14/ RGBow/ IS reporter를 조합하여 뉴런의 형태, 위치, 계통 추적.

l  BrdU, EdU, Raav-Flp 등으로 뉴런 출생 시기와 투사 경로 (시상, 피각, 반대측 피질 등) 분석.

3) Results

3-1) IP는 유사한 두 개의 ‘쌍둥이 뉴런’을 생성

-       동일한 IP에서 유래한 두 개의 뉴런은 같은 층에 위치하고, 형태학적으로 유사함.

-       이는 각 IP가 운명 결정된 (fate-specified) 세포임을 의미.

3-2) 층 배열은 단순한 ‘inside-out’ 구조를 따르지 않음.

-       같은 시기에 생성된 뉴런이 서로 떨어진 층 (L4, L6 등)에 위치하거나, 동일 층에 위치한 뉴런이 서로 다른 시점에 생성됨.

-       이는 여러 시간대의 IP 코호트가 동시에 혹은 순차적으로 작동하여 다양한 PN을 생성함을 시사함.

3-3) 뉴런의 투사 경로와 생성 시기

-       피질-시상/ 척수 투사 뉴런은 주로 초기 (E12.5 ~E13.5)에 생성.

-       피질-피질/선조체 뉴런은 중후기 (E14.5 ~ E18.5)에 걸쳐 생성됨.

-       같은 층 내에서도 형태 및 기능적으로 다른 뉴런들이 존재함.

 3-4)  L4 뉴런의 형태 다양성

-       E14.0 시점에서 생성된 L4 뉴런은 대부분 spiny stellate neurons, E15.5에는 pyramidal neurons이 주로 생성됨.