Meier–Gorlin syndrome and Wolf–Hirschhorn syndrome: Two developmental disorders highlighting the importance of efficient DNA replication for normal development and neurogenesis

Causes and consequences of replication stress

“…For example, in mice the MCM4 Chaos allele destabilizes the MCM complex, reducing the number of licensed origins and increasing genomic instability due to the persistence of stalled replication forks 4,76,122 . In humans, mutations in several origin licensing proteins, including the origin recognition complex (ORC), cause the developmental disorder Meier-Gorlin Syndrome (Table 1), although the effects of these mutations could reflect roles for ORC complex proteins outside of origin licensing 123,124 . In addition, mutations which affect histone deposition and replication fork speed are also associated with the human diseases Wolf–Hirschhorn syndrome 125,126 and congenital dyserythropoietic anaemia type I 127 (Table 1).…”

“…This includes Microcephalic Primordial Dwarfisms, such as Meier-Gorlan syndrome 124,128 , multi-organ dysfunction syndromes affecting primary cilia, known as ciliopathies 129–132 , and human aging conditions associated with mutation of the lamin proteins, or laminopathies 133 (Table 1). The effects of replication stress on the development of these atypical diseases opens up exciting new avenues to explore in the future.…”

Exploring the developmental mechanisms underlying Wolf-Hirschhorn Syndrome: Evidence for defects in neural crest cell migration

“…The importance of TACC3 at the mitotic spindle calls to attention a particular phenotype characteristic of WHS: microcephaly, or reduced occipital frontal circumference, is a well-documented outcome of spindle dysregulation (Kerzendorfer et al, 2013; Mahmood et al, 2011; Megraw et al, 2011; Thornton and Woods, 2009; Fig. 2C).…”

“…2C). The link between microcephaly and spindle pole microtubules is substantiated by the observation that all microcephaly-associated genetic defects identified thus far involve proteins with known or predicted roles in forming or maintaining centrosomes and the spindle apparatus (Kerzendorfer et al, 2013). The influence that spindle regulation has on determination of cerebral size is perhaps most clear in the example of ASPM, or abnormal spindle-like microcephaly-associated protein.…”

“…Knockdown of ASPM by RNA interference in mouse neuroepithelial cells results in skewed spindle pole orientation, preventing one daughter cell from inheriting apical membrane and ultimately preventing the pool of neuroepithelial progenitors from expanding; this reduced progenitor pool size could very well be an early developmental determinant of microcephaly (Fish et al, 2006). As Kerzendorfer et al point out, progenitor cells’ transition from symmetric to asymmetric division is tightly regulated, so that differentiation and subsequent migration to the appropriate tissue occur normally (Kerzendorfer et al, 2013). Going forward, it will be constructive to examine whether TACC3 and other plus-end tracking proteins (+TIPs) at the mitotic spindle are capable of altering its morphology such that cell fate and migration are impacted, and whether changes in these processes contribute to the defects seen in WHS.…”