Mcph1, mutated in primary microcephaly, is also crucial for erythropoiesis

TL;DR

The Mcph1 gene is crucial for both brain development and red blood cell formation, and its loss causes anemia and microcephaly in mice.

Contribution

This study reveals that Mcph1 is essential for erythropoiesis and shares pathophysiological mechanisms with neurogenesis defects.

Findings

Mcph1 deficiency causes congenital macrocytic anemia due to impaired terminal erythroid differentiation.

Loss of Mcph1 leads to acytokinetic mitosis in both erythroid and neural progenitor cells.

p53 activation occurs in Mcph1-deficient cells but does not cause anemia or microcephaly.

Abstract

Microcephaly is a common feature in inherited bone marrow failure syndromes, prompting investigations into shared pathways between neurogenesis and hematopoiesis. To understand this association, we studied the role of the microcephaly gene Mcph1 in hematological development. Our research revealed that Mcph1-knockout mice exhibited congenital macrocytic anemia due to impaired terminal erythroid differentiation during fetal development. Anemia’s cause is a failure to complete cell division, evident from tetraploid erythroid progenitors with DNA content exceeding 4n. Gene expression profiling demonstrated activation of the p53 pathway in Mcph1-deficient erythroid precursors, leading to overexpression of Cdkn1a/p21, a major mediator of p53-dependent cell cycle arrest. Surprisingly, fetal brain analysis revealed hypertrophied binucleated neuroprogenitors overexpressing p21 in Mcph1-knockout mice, indicating a shared pathophysiological mechanism underlying both erythroid and neurological defects. However, inactivating p53 in Mcph1−/− mice failed to reverse anemia and microcephaly, suggesting that p53 activation in Mcph1-deficient cells resulted from their proliferation defect rather than causing it. These findings shed new light on Mcph1’s function in fetal hematopoietic development, emphasizing the impact of disrupted cell division on neurogenesis and erythropoiesis — a common limiting pathway.

Mcph1, known to be required for proper neurogenesis, is also essential for erythropoiesis. Biallelic loss of Mcph1 results in a p53-independent disruption of mitosis, ultimately leading to microcephaly and severe congenital anemia.

Mcph1 deficiency leads to congenital dyserythropoietic anemia in mice.Loss of Mcph1 in erythroid precursors induces acytokinetic mitosis during differentiation.Acytokinetic mitosis also occurs in neural progenitors in the absence of Mcph1.Loss of Mcph1 leads to p53 activation in both erythroid and neuroprogenitors cells.p53 inactivation fails to reverse anemia and microcephaly.

Mcph1 deficiency leads to congenital dyserythropoietic anemia in mice.

Loss of Mcph1 in erythroid precursors induces acytokinetic mitosis during differentiation.

Acytokinetic mitosis also occurs in neural progenitors in the absence of Mcph1.

Loss of Mcph1 leads to p53 activation in both erythroid and neuroprogenitors cells.

p53 inactivation fails to reverse anemia and microcephaly.

Mcph1, known to be required for proper neurogenesis, is also essential for erythropoiesis. Biallelic loss of Mcph1 results in a p53-independent disruption of mitosis, ultimately leading to microcephaly and severe congenital anemia.

Figures