Impaired neurogenesis alters brain biomechanics in a neuropregenitor-based genetic subtype of congenital hydrocephalus

1. 논문 제목: Impaired neurogenesis alters brain biomechanics in a neuropregenitor-based genetic subtype of congenital hydrocephalus

2. 저자명: Phan Q. Duy, Stefan C. Weise, Claudia Marini, Xiao-Jun Li, Dan Liang, Peter J. Dahl, Shaojie Ma, Ana Spajic, Weilai Dong, Jane Juusola, Emre Kiziltug, Adam J. Kundishora, Sunil Koundal, Maysam Z. Pedram, Lucia A. Torres-Fernández, Kristian Händler, Elena De Domenico, Matthias Becker, Thomas Ulas, Stefan A. Juranek, Elisa Cuevas, Le Thi Hao, Bettina Jux, André M. M. Sousa, Fuchen Liu, Suel-Kee Kim, Mingfeng Li, Yiying Yang, Yutaka Takeo, Alvaro Duque, Carol Nelson-Williams, Yonghyun Ha, Kartiga Selvaganesan, Stephanie M. Robert, Amrita K. Singh, Garrett Allington, Charuta G. Furey, Andrew T. Timberlake, Benjamin C. Reeves, Hannah Smith, Ashley Dunbar, Tyrone DeSpenza Jr., June Goto, Arnaud Marlier, Andres Moreno-De-Luca, Xin Yu, William E. Butler, Bob S. Carter, Evelyn M. R. Lake, R. Todd Constable, Pasko Rakic, Haifan Lin, Engin Deniz, Helene Benveniste, Nikhil S. Malvankar, Juvianee I. Estrada-Veras, Christopher A. Walsh, Seth L. Alper, Joachim L. Schultze, Katrin Paeschke, Angelika Doetzlhofer, F. Gregory Wulczyn, Sheng Chih Jin, Richard P. Lifton, Nenad Sestan, Waldemar Kolanus and Kristopher T. Kahle

3. 출처 및 게재 (발행일): Nature communications, 04 April 2022

4. DOI: https://doi.org/10.1038/s41593-022-01043-3

5. Abstract:

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain–CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

6. 한글 초록 요약본:

 본 연구는 선천성 수두증의 한 유전형 모델에서 신경전구세포 기능 저해 -> 신경발생 장애 -> 뇌역학적 특성 변화 -> 수두증 발생 이라는 인과적 연결을 규명하는 것을 목적으로 함. 돌연변이 모델에서 뇌실 확장과 함께 피질 두께 감소, ECM 구성 변화, 조직 탄성 변화가 확인되었으며, 이는 전통적 choroid plexus 중심 CSF 과잉 생산 모델로 설명되지 않는 새로운 병태임. 즉, 수두증은 단순히 CSF 흐름 장애가 아니라 신경 발생 실패로 인한 뇌 구조, 기계적 취약성에 의해 유발될 수 있음을 보여줌.

7. 한글 논문 요약본 (Intro, Methods, Results)

1) Introduction: 선천성 수두증은 전통적으로 CSF 흐름 장애로 설명되어 왔지만, 일부 환자에서는 명확한 순환 이상이 발견되지 않음. 최근 연구는 신경발생 관련 유전자 변이가 수두증과 연관됨을 보여주며, 뇌 발달 자체의 실패가 병인을 형성할 가능성이 제기되고 있음. 이 연구는 신경전구세포 손상이 뇌조직 구조 및 생역학을 변화시켜 수두증을 유발할 수 있다는 새로운 가설을 검증하고 수행됨.

2) Methods: 단순 뇌실 크기 평가가 아니라 세포, 조직, 기계적 특성까지 계층적으로 분석함.

 2-1) 신경발생률: BrdU/EdU labeling, Sox2/Nestin 세포 정량

 2-2) 뇌 구조/ 형태: MRI로 뇌실 크기 및 cortical thickness 분석 

 2-3) 생역학적 특성: AFM (탄성/강도), indentation test

 2-4) ECM 변화: 콜라겐/ 엘라스틴 염색 및 구성 비교

 2-5) CSF 요인 확인: choroid plexus 형태, ICP 측정

3) Results

3-1) 신경발생 저하: 실험 모델에서 Sox2, Nestin 양성 신경전구세포 수가 감소했고, BrdU/EdU 분석에서도 세포 증식과 뉴런 생성이 전반적으로 줄어든 것을 확인함. 이러한 변화는 피질 형성 과정에 영향을 미쳐 실제로 cortical thickness가 감소하고 층 구조가 완전하게 형성되지 못함.

3-2) 뇌실 확장 발생: MRI 분석에서는 뚜렷한 뇌실 확장이 관찰됨. 그러나 ICP 상승이나 CSF 생성량 증가는 크지 않았으며, choroid plexus 구조도 비교적 정상 범위를 유지함. 이는 뇌실 확대가 CSF 압력 문제보다는 뇌조직 자체의 변화와 관련될 가능성을 보여줌.

3-3) 뇌조직의 기계적 강도 저하가 확인됨: AFM 측정에서는 뇌조직의 stiffness가 낮아져 외부 압력에 대한 저항성이 감소된 상태가 확인됨. ECM 분석에서도 콜라겐 섬유량 감소 등 조직 지지 구조가 약해지는 양상이 나타남. 이는 뇌가 물리적으로 더 연약해져 적은 힘에도 쉽게 확장될 수 있는 환경이 조성되었음을 의미함.

8. 대표 figure

Figure 8. Graphical summary of finding.